Orthovoltage radiotherapy

ABSTRACT

A radiosurgery system is described that is configured to deliver a therapeutic dose of radiation to a target structure in a patient. In some embodiments, the target tissues are placed in a global coordinate system based on ocular imaging. In some embodiments, a treatment plan is utilized in which beam energy and direction and duration of time for treatment is determined for a specific disease to be treated and/or structures to be avoided. In some embodiments, a fiducial marker is used to identify the location of the target tissues. In some embodiments, radiodynamic therapy is described in which radiosurgery is used in combination with other treatments and can be delivered concomitant with, prior to, or following other treatments.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/493,136, filed Jun. 26, 2009, now U.S. Pat. No. 7,978,818, which is acontinuation of U.S. patent application Ser. No. 11/956,295, filed Dec.13, 2007, now U.S. Pat. No. 7,620,147, which claims priority benefit ofU.S. Provisional Application No. 60/933,220, filed Jun. 4, 2007; U.S.Provisional Application No. 60/922,741, filed Apr. 9, 2007; and U.S.Provisional Application No. 60/869,872, filed Dec. 13, 2006; theentirety of each of which is incorporated herein by reference.

BACKGROUND

1. Field of the Inventions

This disclosure relates to the treatment of ocular disorders usingtargeted photon energy. In particular, the present disclosure relates toapparatus, systems, and methods for image-guided low energy x-raytherapy of ocular structures.

2. Description of the Related Art

Macular degeneration is a condition where the light-sensing cells of themacula, a near-center portion of the retina of the human eye,malfunction and slowly cease to work. Macular degeneration is theleading cause of central vision loss in people over the age of fiftyyears. Clinical and histologic evidence indicates that maculardegeneration is in part caused by or results in an inflammatory processthat ultimately causes destruction of the retina. The inflammatoryprocess can result in direct destruction of the retina or destructionvia formation of neovascular membranes which leak fluid and blood intothe retina, quickly leading to scarring.

Many treatments for macular degeneration are aimed at stopping theneovascular (or “wet”) form of macular degeneration rather thangeographic atrophy, or the “dry” form of Age-related MacularDegeneration (AMD). All wet AMD begins as dry AMD. Indeed, the currenttrend in advanced ophthalmic imaging is that wet AMD is being identifiedprior to loss of visual acuity. Treatments for macular degenerationinclude the use of medication injected directly into the eye (Anti-VEGFtherapy) and laser therapy in combination with a targeting drug(photodynamic therapy); other treatments include brachytherapy (i.e.,the local application of a material which generates beta-radiation).

SUMMARY

Disclosed herein are systems, methods, and apparatus that providetreatment for ocular disorders by irradiating specific regions of theeye without substantially exposing the rest of the eye to radiation. Insome embodiments described herein, radiotherapy systems are disclosedthat may be used to treat a wide variety of medical conditions relatingto the eye. For example, the systems may be used, alone or incombination with other therapies, to treat macular degeneration,diabetic retinopathy, inflammatory retinopathies, infectiousretinopathies, tumors in the eye or around the eye, glaucoma, refractivedisorders, cataracts, post-surgical inflammation of any of thestructures of the eye, ptyrigium, and dry eye.

In some embodiments described herein, radiotherapy (or externallyapplied radiation therapy) is used for treatment of maculardegeneration, and standard treatments for macular degeneration aredisclosed. Radiotherapy treatment of macular degeneration presentsseveral complications. For example, the eye contains several criticalstructures, such as the lens and the optic nerve, that can possibly bedamaged by excessive exposure to radiation. The application of externalbeam therapy is limited by devices and methodologies used to apply thetherapy. These devices and methodologies are older radiationtechnologies used to treat conditions such as tumors anywhere in thebody and were not developed specifically for ocular radiation therapy.In addition, logistics are difficult as far as patient recruitment andadministration of treatments because such treatment devices are borrowedfrom and displace oncologic therapies.

Stereotactic radiation therapy generally refers to the delivery ofradiation beams from multiple directions to focus on a target. Suchtherapy is delivered using large linear accelerators or radioactivesources, such as Cobalt-60 (gamma knife) Robotic stereotactic surgery(e.g., see U.S. patent application Ser. No. 11/354,411, filed Feb. 14,2006, entitled, “Adaptive X-ray Control,” assigned to Accuray Inc., theentirety of which is hereby incorporated by reference) is an applicationof stereotactic radiation in which a large linear accelerator movesabout a patient and delivers a series of radiation beams toward atarget. Because the dose can be controlled around the target, whilesparing normal tissue, the therapy can be delivered in a small number offractionated doses. The procedure may be referred to as “radiosurgery”versus radiotherapy. In general terms, radiosurgery is one form ofradiation therapy.

Retinal radiotherapy trials have shown stabilized or improved visualacuity without any significant toxicity. Radiation has also been shownto dry up neovascular membranes in patients and stabilize vision.However, due to limitations in the treatment of macular degenerationusing radiotherapy, including localization of the region to be treatedas well as specific application of the radiation to the region to betreated, macular radiotherapy often irradiates the entire retina, whichis both unnecessary and possibly harmful. Moreover, the dose ofradiation specifically to the macula has not been limited to multiplefractions over many days or weeks. The ability to apply a greater dosespecifically to the macula in a period of time less than 24 hours willhave a greater effect on the disease than was shown in previous trials.

Brachytherapy for wet AMD is also a powerful therapy to treat wet AMD(Neovista, Inc., Press Release, March 2007, the entirety of which isincorporated herein by reference). A major limitation of this treatmentis that it requires invasive procedures involving partial removal of thevitreous fluid of the posterior chamber of the eye to place thebrachytherapy probe. In addition, the ability to fractionate the dose islimited because of the invasiveness required to deliver the therapy.Furthermore, the therapy is dependent on exact placement by the surgeonand the stability of the surgeon's hand.

Other diseases of the eye include glaucoma. In this disease, surgery isoften the second line of therapy after pharmaceutical therapy.Procedures such as trabeculoplasty, trabeculotomy, canaloplasty, laseriridotomy, placement of shunts, and other procedures all suffer from ashort-lived effect because of scar formation as a result of the surgicaltrauma. Anti-inflammatory drugs appear to offer a palliative and/orpreventative solution to the chronic scarring that occurs after theseprocedures; however, the drugs have to be given several times per dayand are associated with their own side effect profile such as seepageinto unwanted regions of the eye. Radiation doses (e.g., from about 5 Gyto about 20 Gy in some instances and about 10 Gy some embodiments) canbe beneficial in the prevention of scarring after glaucoma surgery (see,e.g., Kirwan, et. al., Effect of Beta Radiation on Success of GlaucomaDrainage Surgery in South Africa: randomized controlled trial; BritishMedical Journal, Oct. 5, 2006, the entirety of which is hereinincorporated by reference). Capsular opacification is a commonoccurrence after cataract procedures with placement of intra-ocularlenses (add reference). This scarring is caused by trauma from thesurgery, proliferation of lens cells, and material incompatibility.

Another disease of the eye that is treatable with the systems, methods,and apparatus disclosed herein is pterygia of the eye. A pterygium is anelevated, superficial, external ocular mass that usually forms over theperilimbal conjunctiva and extends onto the corneal surface. Pterygiacan vary from small, atrophic quiescent lesions to large, aggressive,rapidly growing fibrovascular lesions that can distort the cornealtopography, and in advanced cases, can obscure the optical center of thecornea. The exact cause of pterygia is not well understood, although itoccurs more often in people who spend a great deal of time outdoors,especially in sunny climates, and has been linked to long-term exposureto sunlight, especially ultraviolet rays, and chronic eye irritationfrom dry, dusty, and windy conditions. Pterygia can become inflamed, andthe symptoms are often treated with topical eyedrops or ointments thatcan help to reduce the inflammation. If the pterygium is large enough tothreaten sight, or encroaches on the cornea, the lesion is typicallytreated by surgical removal before vision is affected. However, evenwith most surgical techniques, the recurrence rate is often as high as50 to 60 percent. The systems, methods, and apparatus disclosed hereincan be used postoperatively to reduce the likelihood of recurrence of apterygium by administration of radiation doses, and in some embodiments,doses of radiation can be used to slow or stop progression of thepterygium prior to surgery. (See, e.g., “Long-term results ofnon-surgical, exclusive strontium/yytrium-90 beta irradiation ofpterygia,” Radiation and Oncology 74 (2005) 25-29; the entirety of whichis incorporated herein by reference).

In some embodiments, the radiation treatment system is usedconcomitantly with laser therapy. That is, rather than using a lasersolely for pointing the x-ray device to the ocular target of choice, thelaser is used for both pointing and therapy. In these embodiments, thelaser preferably includes at least one additional energy or wavelengthsuitable for therapy of an ocular structure. The x-ray is preferablyapplied to the same region as the laser so as to limit or reduceexcessive scarring around the laser therapy. For example, someembodiments of the systems and methods can be used in connection withglaucoma treatment, such as, for example, a trabeculectomy, in which thelaser is used to create perforations or apertures in the trabecularmeshwork of an eye while the x-ray, or radiation doses, are applied tolimit or reduce scarring.

In some embodiments, the system can be configured to provide a source ofheat, to heat the target tissue, and the x-rays are applied inconjunction with the heating of the target tissue. The term “applying inconjunction,” in this context, can be applying the x-rays in preparationfor applying the heat to the tissue, applying the x-rays followingapplying the heat to the tissue, or applying the x-rays at the same timeas heat is applied to the tissue. The x-rays can be applied from about 2and about 10 days prior to the treatment of the heat, and in someembodiments, the x-rays can be applied from about 2 and about 10 daysfollowing the treatment of the heat. In some embodiments, the x-rays areapplied in a period that is less than about 2 days prior to treatment ofthe heat, and in some embodiments, the x-rays are applied in a periodthat is less than about 2 days following the treatment of the heat. Insome embodiments, the x-rays are applied more than about 10 days priorto treatment of the tissue with heat, and in some embodiments, thex-rays are applied more than about 10 days following treatment of thetissue with heat. In some embodiments, variations of these treatmentmethods may be used. For example, multiple treatments of the targettissue with heat can be applied before and after the x-ray application.In another example, multiple treatments of the target tissue with x-rayscan be applied before and after the treatment of the target tissue withheat. In some embodiments, treatment at substantially the same time caninclude treatment of the target tissue with heat and x-rays within about72 hours, 48 hours, 36 hours, 24 hours, 12 hours, 6 hours, 2 hours, 1hour, 30 minutes, 10 minutes, and 1 minute of each other. In someembodiments, treatment at substantially the same time can includetreatment of the target tissue with heat and x-rays within about 1 week,2 weeks, 3 weeks, and a month of each other.

In some embodiments, laser therapy is applied through a needle, theneedle penetrating through eye tissue. For example, a needle or cannulacan be placed through the sclera of the eye and into the vitreous todeliver a drug. The needle or cannula can also be used to direct a lightpointer beam such as a laser pointer. The light pointer can be pointedto the retina and the lighted region on the retina visualized through alens. A radiotherapy device can then be aligned, such as, for example,to be collinear, with the cannula and an x-ray beam can be emitted in analigned trajectory with the laser pointer and intersect the retina atthe same place as the laser pointer. In these embodiments, a target onthe retina can be identified, targeted, and treated with the systems,methods, and apparatus described herein.

In some embodiments of this disclosure, electromotive and ocular imagingsystems are utilized, but laser therapy is the sole radiation energysource used for treatment. In these embodiments, the ability of thesystem to focus radiation by passing the photons through the sclera fromdifferent angles to structures deep to the sclera can be utilized totreat diseases of the anterior chamber or posterior chamber with laserradiation while keeping the x-ray generation system off. In someembodiments, the x-ray generator is not included in the system. In theseembodiments, the eye model, tracking, control, and focusing systems forthe x-ray therapy are utilized for laser therapy.

In certain embodiments, a device, using a treatment planning system, isdisclosed for providing targeted radiotherapy to specific regions of theeye. The treatment planning system integrates physical variables of theeye and disease variables from the physician to direct the x-ray systemto deliver therapy to the ocular structures. The device applies narrowbeams of radiation from one or more angles to focus radiation to atargeted region of the eye. In certain embodiments, the device may focusradiation beams to structures of the posterior eye, such as the retina.In certain embodiments, the device may focus radiation beams tostructures of the anterior region of the eye, such as the sclera, thecornea, or the trabecular meshwork. The treatment planning system allowsfor planning of the direction of the beam entry into the eye atdifferent points along the eye's surface, for example, the sclera. Theunique anatomy of each individual is integrated into the treatmentplanning system for accurate targeting, and in some instances, automatedpositioning and orienting of the x-ray beams of the device.

In some embodiments described herein, treatment systems are provided fordelivering radiation to a patient that include an eye model derived fromanatomic data of a patient's eye, an emitter that emits a radiationbeam, and a position guide, coupled to the emitter, that positions,based on the eye model, the emitter with respect to a location on or inthe eye, such that the radiation beam is delivered to a target on or inthe eye.

In some embodiments, the location comprises the target. The emitter canbe configured to deliver the radiation beam with a photon energy betweenabout 10 keV and about 500 keV or to deliver an radiation beamadjustable between about 25 keV and about 100 keV. In some embodiments,the radiation beam includes an x-ray beam. In some embodiments, thesystem further includes a planning module configured to determine, basedon the eye model, at least two of a beam target, a beam intensity, abeam energy, a beam trajectory, a treatment field size, a treatmentfield shape, a distance from the emitter to the target, an exposuretime, and a dose.

The position guide, in some embodiments, positions the emitter, based oninformation from the planning module, such that the emitter directs afirst radiation beam at a first position through a first portion of theeye to a treatment region within the eye. The position guide preferablypositions the emitter, based on information from the planning module,such that the emitter directs a second radiation beam at a secondposition through a second portion of the eye to the treatment regionwithin the eye. In some embodiments, the planning module is adapted toreceive input from a user, the input affecting an output of the planningmodule. In some embodiments, the system includes a sensing module thatsenses a position of the eye and relays information concerning theposition of the eye to the planning module.

The system includes, in some embodiments, a sensing module that senses aposition of the eye and relays information concerning the position ofthe eye to the position guide. The sensing module can include a portionthat physically contacts the eye, which can include a lens positionableon or over the cornea of the eye. The sensing module can, in someembodiments, optically sense the position of the eye with, for example,a laser.

In some embodiments, the system also includes a collimator thatcollimates the radiation beam to a width of from about 0.5 mm to about 6mm. The collimated beam can also have a penumbra of less than about tenpercent at a distance up to about 50 cm from the collimator. Theposition guide, in some embodiments, is configured to position theemitter, in use, at a first distance within 50 cm of the target, suchthat the emitter delivers the radiation beam to the target from thefirst distance. In some embodiments, a collimator is positioned, in use,to within about 10 cm of the target when the radiation beam is deliveredto the target.

The system can further include a detector that detects if the patient'seye moves such that the radiation beam is not directed to the target. Insome embodiments, the emitter is configured to automatically not emitthe radiation beam if the patient's eye moves out of a predeterminedposition or range of positions. Some embodiments include a laser emitterthat emits a laser beam that passes through a collimator and is directedtoward the eye and in some embodiments, is applied along the same axisas the x-ray emitter.

Some embodiments described herein disclose a system for deliveringradiation to an eye that includes an eye model derived from anatomicdata of a patient's eye, an emitter that delivers an x-ray beam to theeye with an energy from about 10 keV to about 500 keV, a position guide,coupled to the emitter, that positions, based on the eye model, theemitter with respect to a location in or on the eye, to deliver thex-ray beam to a target in or on the eye, and a planning module thatdetermines at least two parameters of treatment based on the model ofthe eye. In some embodiments, the at least two parameters include two ofa beam target, a beam intensity, a beam energy, a beam trajectory, atreatment field size, a treatment field shape, a distance from theemitter to the target, an exposure time, and a dose.

The position guide, in some embodiments, is configured to direct a firstx-ray beam from a first position to a first region of a sclera of theeye to target a region of the eye, and is further configured to direct asecond x-ray beam from a second position to a second region of thesclera to target substantially the same region of the eye. In someembodiments, the region of the eye is at least one of the macula, thesclera, the trabecular meshwork, and a capsule of the lens of the eye.

The system can further include a collimator that collimates the x-raybeam. In some embodiments, the collimator is configured to collimate thex-ray beam to a width of from about 0.5 mm to about 6 mm, and in someembodiments, the system is configured to produce an x-ray beam having apenumbra of less than about five percent within a distance, from thecollimator to the target, of about 50 cm. The emitter, in someembodiments, is configured to deliver an x-ray beam with a photon energybetween about 25 keV and about 150 keV. In some embodiments, thecollimator is positioned, in use, to within about 10 cm of the targetwhen the x-ray beam is delivered to the target.

In some embodiments, a treatment system for delivering radiation to ahuman being is provided, the system including an eye model derived fromanatomic data of a patient's eye; an emitter that delivers an x-ray beamto the eye; and means for positioning the emitter, with respect to alocation on or in the eye, to deliver the x-ray beam to a target on orin the eye, the means being coupled to the emitter, and the positioningof the emitter being based on the eye model.

Some embodiments provide a treatment system for delivering radiation toa patient that includes an emitter that generates a radiation beam, anda position guide, coupled to the emitter, operable to positions theemitter with respect to a location on or in the eye, to deliver theradiation beam to a target on or in the eye, wherein the emitter isplaced within 50 cm of the target. In some embodiments, the systemfurther includes a collimator coupled to the emitter, the collimatorbeing placed, in use, to within 10 cm of the target when the emitteremits the radiation beam. In some embodiments, the system furtherincludes a collimated laser emitter that is coupled to the emitter.

In some embodiments described herein, a method of treating maculardegeneration of an eye is disclosed. The method preferably includesproviding a model of an eye of a patient with anatomic data obtained byan imaging apparatus, producing an x-ray beam with a width of from about0.5 mm to about 6 mm and having a photon energy between about 40 keV andabout 100 keV, and in some embodiments between about 40 keV and about250 keV, directing the x-ray beam such that the beam passes through thesclera to the retina of the eye, and exposing the retina to from about 1Gy to about 40 Gy of x-ray radiation.

In some embodiments, the method provides that at least one of the x-raybeam width, photon energy, and direction of the x-ray beam is determinedbased on the model of the eye. The method further provides, in someembodiments, that the retina is exposed to from about 15 Gy to about 25Gy of x-ray radiation. In some embodiments, treatment with the x-rayradiation can be fractionated, and a planning system can keep track ofthe quantity and location of prior treatments. In some embodiments, themethod includes reducing neovascularization in the eye by exposing theretina to the radiation. The method may further include administering tothe patient at least one of heating, cooling, vascular endothelialgrowth factor (VEGF) antagonist, a VEGF-receptor antagonist, an antibodydirected to VEGF or a VEGF receptor, a modality which increases DNAstrand breaks or decreases DNA repair, a modality which increases thelevel of apoptosis, a modality which increases endothelial cell death, ataxane or other microtubule inhibitor, a topoisomerase inhibitor such asirinotecan, a pharmaceutical in the limus family such as sirolimus, acompound which methylates DNA such as temozolomide, an analogue orprodrug of 5-fluorouracil such as capecitabine, a free radical inducingagent such as tirapazamine, small molecule tyrosine kinase inhibitorssuch as gefitinib or erlotinib, NFκB inhibitors or downregulators suchas bortezomib, microwave energy, laser energy, hyperbaric oxygen,supersaturated oxygen, ultrasound energy, radiofrequency energy, and atherapeutic agent, prior to, or after, exposing the retina to theradiation. The method further includes, in some embodiments, directing afirst x-ray beam to pass through the sclera to the retina from a firstposition external to the eye, and directing a second x-ray beam to passthrough the sclera to the retina from a second position external to theeye. In some embodiments, the x-ray beam is directed to pass through apars plana of the eye. The x-ray beam is, in some embodiments, directedto a macula of the eye.

Some embodiments herein describe a method of treating an eye of apatient that includes providing a model of the eye based on anatomicdata obtained by an imaging apparatus, producing a first x-ray beam anda second x-ray beam, each beam having a width of from about 0.5 mm toabout 6 mm, directing the first x-ray beam such that the first beampasses through a first region of a sclera of the eye to a target of aretina, and directing the second x-ray beam such that the second beampasses through a second region of the sclera to substantially the sametarget of the retina as the first beam, wherein the first region andsecond region of the sclera through which the first beam and second beampass are selected based on the model of the eye.

In some embodiments, a trajectory of the first beam is determined basedon the model of the eye, and in some embodiments, the directing of thefirst x-ray beam and the directing of the second x-ray beam occursequentially. In some embodiments, the first x-ray beam and the secondx-ray beam have photon energies of from about 25 keV to about 100 keV.Centers of the first and second x-ray beams, in some embodiments, areprojected through a point on the sclera at a distance of from about 0.5mm to about 6 mm from a limbus of the eye. In some embodiments, themethod further includes administering to the patient at least one ofheating, cooling, VEGF antagonist, a VEGF-receptor antagonist, anantibody directed to VEGF or a VEGF receptor, microwave energy,radiofrequency energy, laser energy, and a therapeutic agent, prior to,concurrently with, or subsequent to the directing of the first x-raybeam. The x-ray beam, in some embodiments, is produced by an x-raysource positioned less than about 50 cm from the retina. In someembodiments, the x-ray beam is emitted from a source having an end thatis placed within about 10 cm of the eye. In some embodiments, the retinais exposed to about 15 Gy to about 25 Gy in some embodiments, and, insome embodiments to about 35 Gy, of x-ray radiation during one treatmentsession.

Some embodiments described herein relate to a method of treating an eyeof a patient that includes providing a model of the eye based onanatomic data obtained by an imaging apparatus, producing a first x-raybeam and a second x-ray beam, each beam having a width of from about 0.5mm to about 6 mm, directing the first x-ray beam such that the firstbeam passes through a first region of the eye to a target within theeye, and directing the second x-ray beam such that the second beampasses through a second region of the eye to substantially the sametarget within the eye, wherein the first region and second region of theeye through which the first beam and second beam pass are selected basedon the model of the eye.

The target, in some embodiments, includes the lens capsule of the eye.In some embodiments, the target includes the trabecular meshwork of theeye or a tumor. In some embodiments, the first region comprises thecornea of the eye. In some embodiments, the first x-ray beam and thesecond x-ray beam have photon energies of from about 25 keV to about 100keV. In some embodiments, the first and second x-ray beams arecollimated by a collimator positioned within 10 cm of the eye, and insome embodiments, the x-ray beams are produced by an x-ray sourcepositioned within 10 cm of the eye. The x-ray source can also bepositioned within 50, 40, and/or 10 cm of the eye.

In some embodiments, the first region of the eye includes a first regionof a sclera and the second region of the eye comprises a second regionof the sclera, and an edge-to-edge distance from the first region of thesclera to the second region of the sclera is from about 0.1 mm to about2 mm. In some embodiments, the first and second x-ray beams are directedfrom a nasal region external to the eye. Some methods further includealigning the center of the patient's eye with the x-ray radiotherapysystem. Some methods also include developing a plan to treat a macularregion using the model of the eye, wherein the first and second x-raybeams overlap at the macular region, and the first and second x-raybeams are collimated to from about 0.5 mm to about 6 mm.

Some embodiments described herein disclose a method of applyingradiation to the retina of a patient's eye, the method includinglocalizing the macula of the patient with an imaging device, linking themacula to a global coordinate system, and applying an external beam ofradiation to the macula based on the coordinate system.

Some embodiments further include contacting a material to the sclera ofthe eye, the material being linked or trackable to the global coordinatesystem. In certain embodiments, motion of the external beam radiation isautomated based on the coordinate system. In some embodiments, themethod also includes detecting eye movements. Some embodiments furtherinclude recalculating the relationship between the macula and thecoordinate system after a detection of eye movement. In someembodiments, the method further includes implanting a fiducial markerinside the eye to couple the eye and the retina to the coordinatesystem. In some embodiments, the external beam radiation is focusedexternal beam radiation.

Described herein are embodiments that disclose a method of planningradiation treatment to an eye of a patient. In some embodiments, themethod includes obtaining imaging data of the retina of the patient,coupling the imaging data to a global coordinate system, using a laserto enable alignment and targeting of focused ionizing radiation beams tothe retina, and applying automated focused external beam therapy to theretina based on the position of the retina in the global coordinatesystem.

Some embodiments provide a method of treating a region of an eye of apatient that includes producing an x-ray beam with a width of from about0.5 mm to about 6 mm and having a photon energy between about 40 keV andabout 250 keV, directing the x-ray beam toward the eye region, andexposing the region to a dose of from about 1 Gy to about 40 Gy of x-rayradiation, thereby treating the region of the eye.

In some embodiments, the method further includes providing a model ofthe eye with anatomic data obtained by an imaging apparatus, wherein atleast one of a width of the x-ray beam, a photon energy of the x-raybeam, and a direction of the x-ray beam is determined based on the modelof the eye. The region, in some embodiments, is exposed to from about 15Gy to about 25 Gy of x-ray radiation, and in some embodiments, theregion includes a retina of the eye. The treating can include reducingneovascularization in the eye by exposing the retina to the radiation,and/or substantially preventing progression from Dry Age-related MacularDegeneration (AMD) to neovascularization. In some embodiments, themethod also includes administering to the patient at least one ofheating, cooling, VEGF antagonist, a VEGF-receptor antagonist, anantibody directed to VEGF or a VEGF receptor, microwave energy,radiofrequency energy, a laser, a photodynamic agent, and a radiodynamicagent, and a therapeutic agent. Some embodiments further includedirecting a first x-ray beam to pass through a sclera to a retina from afirst position external to the eye, and directing a second x-ray beam topass through the sclera to the retina from a second position external tothe eye. The x-ray beam, in some embodiments, is directed through a parsplana of the eye, and in some embodiments, the x-ray beam is directed toa macula of the eye. The x-ray beam can also be directed through asclera of the eye to the macula of the eye.

Some embodiments provide that the dose is divided between two or morebeams, and in some embodiments, the dose is divided between two or moretreatment sessions, each of said treatment sessions occurring at leastone day apart. Some methods described herein further include determininga position of the eye relative to the x-ray beam during the exposing ofthe region to the x-ray radiation, and shutting off the x-ray beam ifthe position of the eye exceeds a movement threshold.

Some methods of treating an eye of a patient described herein includeproviding a model of the eye based on anatomic data obtained by animaging apparatus, directing a first x-ray beam such that the first beampasses through a first region of the eye to a target within the eye, anddirecting a second x-ray beam such that the second beam passes through asecond region of the eye to substantially the same target within theeye, wherein the first region and second region of the eye through whichthe first beam and second beam pass are selected based on the model ofthe eye, and assessing a position of the eye during at least one of theadministration of the first x-ray beam to the target, administration ofthe second x-ray beam to the target, and a period of time betweenadministration of the first x-ray beam to the target and administrationof the second x-ray beam to the target.

Some methods provide that the assessing occurs during administration ofthe first x-ray beam to the target, and some methods further includeceasing or reducing administration of the first x-ray beam when the eyemoves beyond a movement threshold. Some methods further includedirecting the second x-ray beam based on information from the assessingof the position of the eye.

Some methods provide a method, of planning radiation therapy for an eye,including the steps of preparing a treatment plan for a delivery of anactual dose of radiation to a target at a region of the eye from atleast one radiation beam, the preparing that includes determining afirst estimated dose of radiation, to be delivered from a radiationsource outside the eye to the target; determining a second estimateddose of radiation, to be received by at least one of the optic nerve andthe lens of the eye from the radiation source; and wherein the secondestimated dose of radiation is equal to or less than about 40 percent ofthe first estimated dose; and wherein the treatment plan comprises atleast one of a width of the at least one radiation beam, a distance fromthe radiation source to the target, a trajectory of the beam, a maximumbeam energy, and the first estimated dose of radiation; and wherein theat least one of the width of the at least one radiation beam, thedistance from the radiation source to the target, the trajectory of thebeam is selected to effect delivery of the first estimated dose to thetarget and the second estimated dose to the at least one of the opticnerve and the lens of the eye; and outputting information indicative ofthe treatment plan to an output module.

In some embodiments, at least one of the estimated dose of radiation tobe received at the optic nerve and the estimated dose of radiation to bereceived at the lens is equal to or less than 20 percent of theestimated dose of radiation to be delivered to the target. In someembodiments, at least one of the estimated dose of radiation to bereceived at the optic nerve and the estimated dose of radiation to bereceived at the lens is equal to or less than 10 percent of theestimated dose of radiation to be delivered to the target. In someembodiments, at least one of the estimated dose of radiation to bereceived at the optic nerve and the estimated dose of radiation to bereceived at the lens is equal to or less than 5 percent of the estimateddose of radiation to be delivered to the target. In certain embodiments,at least one of the estimated dose of radiation to be received at theoptic nerve and the estimated dose of radiation to be received at thelens is equal to or less than 1 percent of the estimated dose ofradiation to be delivered to the target.

In certain embodiments, the output module comprises at least one of acomputer monitor, an LCD, an LED, a handheld device, a paper, acomputer-readable medium, a computer-executable instruction, and acommunication link to the radiation source. Some embodiments, furtherincludes delivering thermal energy to the eye during a period of betweenabout 10 days before and about 3 days after delivery of the actual doseof radiation to the target.

In some embodiments, the method further includes delivering the actualdose of radiation to the target. In some embodiments, at least one ofthe estimated dose of radiation to be delivered to the target, theestimated dose of radiation to be received at the optic nerve, and theestimated dose of radiation to be received at the lens is determined bya Monte Carlo simulation. In some embodiments, at least one of the atleast one radiation beam has a cross-sectional shape that is geometric.In some embodiments, the geometric cross-sectional shape comprises atleast one of an ellipse, a circle, a ring, concentric rings, a polygon,and a crescent. In some embodiments, at least one of the estimated doseof radiation to be received at the optic nerve and the estimated dose ofradiation to be received at the lens is based on a surface-to-depth beamenergy representation. In some embodiments, at least one of theestimated dose of radiation to be received at the optic nerve and theestimated dose of radiation to be received at the lens is based ontracing diverging rays from an x-ray source with a maximum beam energyless than about 250 keV.

In some embodiments, a method is disclosed that includes determiningtrajectories of a plurality of radiation beams to be delivered to thetarget, such that each of the plurality of beams traverses the sclera ata respective traversal zone; and wherein none of the traversal zonesoverlaps substantially with any other of the intersection zones.

In some embodiments, at least one of the plurality of beams overlapswith another of the plurality of beams at the target. Some embodimentsfurther include collimating the at least one radiation beam to a sizehaving a cross-sectional dimension that is less than about 6 mm. Someembodiment further include determining a filtration amount such that adose of radiation to an exterior surface of the eye is less than 3 timesa dose of radiation to the target, wherein the at least one radiationbeam having an energy of from about 50 KeV to about 300 KeV.

In some embodiments, the first x-ray beam is filtered with a filterwhich at least partly comprises a heavy metal. Some embodiments, furtherincludes determining a current from about 1 mA to about 40 mA to beapplied to a radiotherapy system such that a therapeutic dose ofradiation to the target is administered in less than about 30 minutes.In some embodiments, the x-ray beam is collimated and wherein saidcollimator is placed within about 20 centimeters of the target. Someembodiments further include determining a direction of the at least oneradiation beam to minimize the estimated dose of radiation to the opticnerve, and wherein the first x-ray beam is delivered from a nasaldirection to a temporal direction or from an inferior direction to asuperior direction with respect to delivery from outside the eye to thetarget inside the eye.

Some embodiments relate to a method, of planning radiation therapy foran eye, including preparing a treatment plan for a delivery of an actualdose of radiation to a target at a region of the eye from at least oneradiation beam, the preparing including: determining a first estimateddose of radiation, to be delivered from a radiation source outside theeye to the target; determining a second estimated dose of radiation, tobe received from the radiation source at other eye tissue, the other eyetissue located less than about 6 mm from a center of the target; andwherein the second estimated dose of radiation is equal to or less thanabout 40 percent of the first estimated dose; and wherein the treatmentplan comprises at least one of a width of the at least one radiationbeam, a distance from the radiation source to the target, a trajectoryof the beam, and the first estimated dose of radiation; and wherein theat least one of the width of the at least one radiation beam, thedistance from the radiation source to the target, the trajectory of thebeam is selected to effect delivery of the first estimated dose to thetarget and the second estimated dose to the other eye tissue; andoutputting information indicative of the treatment plan to an outputmodule.

Some embodiments relate to a method, of treating an eye during atreatment period, including directing radiation from a source outside aneye to a target in or on the retina of the eye, such that a dose ofradiation is emitted during the treatment period to at least one of theoptic nerve and the lens of the eye is no more than about 40 percent ofa dose of radiation delivered to the target. In some embodiments, theradiation is directed substantially through the pars plana of the eye.

In some embodiment a method, of treating an eye during a treatmentperiod, is described that includes directing radiation from a sourceoutside an eye to a target in the eye, such that a dose of radiationemitted during the treatment period to eye tissue located less thanabout 6 mm from a center of the target is no more than about 40 percentof the dose of radiation emitted to the target.

Some embodiments describe a method, of treating inflammation in apatient's eye, including the following: based on data indicative of alocation of a region of inflammation in an eye, directing at least onex-ray beam from a source outside the eye, through an anterior region ofthe eye, to the region of inflammation, such that a dose of radiationemitted during the treatment period to eye tissue greater than about 6mm from a center of the region of inflammation is no more than about 40percent of the dose of radiation emitted to the region of inflammation.

In some embodiments, the region comprises drusen. In some embodiments,the anterior region of the eye is the cornea. In some embodiments, theanterior region of the eye is a sclera outside of a cornea of the eye.In some embodiments, the at least one x-ray beam has a cross-sectionaldimension smaller than about 1 mm. In some embodiments, the beam has adiameter of between about 1 mm and about 5 mm. In some embodiments, theat least one x-ray beam comprises alternating regions of higherintensity and lower intensity. In some embodiments, the method furthercomprising directing a radiotherapy system at the eye at an angle withrespect to a treatment axis that is determined using a device thatcontacts the eye. In some embodiments, the device communicates datarelating to the eye optically with said radiotherapy system. Someembodiments, further include directing a radiotherapy system at the eyeat an angle with respect to a treatment axis that is determined using aneye-contacting device. Some embodiments, further comprising directing aradiotherapy system at the eye at an angle to a treatment axis that isdetermined using one of a reflection of light off the eye, a fundusimage, an image of a pupil of the eye, and an image of a limbus of theeye.

In some embodiments, a method, of delivering radiation to an eye, isdescribed including providing an anterior-posterior axis of the eye;defining a treatment axis relative to the anterior-posterior axis of theeye; aligning a collimator at an angle relative to the treatment axis,the collimator being configured to collimate an x-ray beam that isemitted toward the eye, the collimated x-ray beam having across-sectional dimension of less than about 6 mm; and emitting thex-ray beam at an angle relative to the treatment axis.

In some embodiments, the collimated x-ray beam has a penumbra of lessthan about 20 percent at about 10 cm from the collimator. In someembodiments, the treatment axis is an optical central axis of the eye.In some embodiments, the treatment axis is a visual axis of the eye. Insome embodiments, the treatment axis is perpendicular to a center of thelimbus or cornea. Some embodiments further include moving the collimatedradiation beam relative to the treatment axis and emitting a secondcollimated x-ray beam. Some embodiments further include moving the eyerelative to the collimated radiation beam. Some embodiments, furtherinclude aligning the collimated x-ray beam with a projected spot on thesclera of the eye. In some embodiments, the spot is aligned with thetreatment axis. In some embodiments, the spot is aligned with thecollimated x-ray beam. In some embodiments, emitting the collimatedx-ray beam is based on a treatment planning software program.

In some embodiments, described is a method, of treating an ocularstructure of an eye with a radiation beam from a radiotherapy system,including contacting a surface of the eye with an eye contact member,wherein the eye contact member comprises a first portion, such that anaxis passing through the ocular structure also passes through the firstportion of the eye contact member; and emitting a plurality of radiationbeams toward the ocular structure, from a radiotherapy system locatedoutside the eye, such that the plurality of radiation beams each have atrajectory that intersects the axis at a treatment site at the ocularstructure, the treatment site being effectively treatable by at leastone of the plurality of radiation beams.

Some embodiments further include substantially fixing the eye in a firstposition with the eye contact member. In some embodiments, the eyecontact member comprises a transmissive portion that transmits a firstwavelength of electromagnetic radiation from outside to inside the eye.In some embodiments, the first portion is reflective of a secondwavelength of electromagnetic radiation. In some embodiments, the firstportion is centrally located in or on the eye contact member. In someembodiments, at least one of the plurality of radiation beams compriseslaser light. In some embodiments, In some embodiments, at least one ofthe plurality of radiation beams comprises x-rays.

In some embodiments, described is a patient ocular interface, fortreatment of an ocular structure with a radiotherapy system, includingan eye holder, having an eye-contacting surface that engages an outersurface of an eye, that maintains the eye in substantially a firstposition; and wherein the eye holder is configured to provide anindication to a sensor that the eye is in substantially the firstposition during delivery of a radiation beam from a source, locatedoutside the eye, to the eye.

Some embodiments further include a material that is transmissive of theradiation beam through the ocular interface. In some embodiments, theradiation beam comprises laser light. In some embodiments, the radiationbeam comprises x-rays.

In some embodiments described herein, a patient ocular interface isdescribed, for treatment of an ocular structure with a radiotherapysystem, including: a holder adapted to maintain an eye in asubstantially stable position; and a communication link thatcommunicates information between the holder and a radiotherapy system,the information being indicative of a position of the eye anddetermining a characteristic of a radiation beam emitted from theradiotherapy system.

In some embodiments, the communication link comprises a reflectivematerial that reflects some wavelengths of light. In some embodiments,the characteristic of the radiation beam determined by the informationcomprises at least one of a trajectory of the radiation beam and anemit/not-emit status. In some embodiments, the holder contacts the eye.In some embodiments, the holder is attachable to a surface external tothe eye. In some embodiments, the holder is mechanically linked to theradiotherapy system. In some embodiments, the communication link to theradiotherapy system is an optical link. In some embodiments, the holderis adapted to align the radiotherapy system with an axis of the eye. Insome embodiments, the holder is adapted to align the radiotherapy systemwith a visual axis of the eye. Some embodiments, further include acamera that visualizes a position of the eye relative to the holder. Insome embodiments, the camera detects movement of the eye andcommunicates data relating to the eye's movement with imaging software.

In some embodiments, the holder contacts the sclera. In someembodiments, the holder contacts the cornea. In some embodiments, theholder is at least partially opaque to x-ray energy. In someembodiments, the holder is at least partially transparent to x-rayenergy. In some embodiments, the holder is configured to apply a suctionto the eye.

In some embodiments, a system is described, for delivery of an x-raybeam to an eye of a patient, including at least one x-ray collimatorthat, in use, is placed within about 15 cm of a retina; and a laser thatemits a laser beam that is substantially aligned with a long axis of thecollimator and that provides an indication, on at least one of a surfaceof the eye and a device in contact with a surface of the eye, of adirection of an x-ray beam emitted through the collimator.

In some embodiments, the system further comprising a power supplyadapted to deliver between about 10 mA and about 800 mA of current tothe anode of an x-ray tube that delivers the x-ray beam. In someembodiments, the anode is one of a stationary anode and a rotatinganode. Some embodiments further include an eye contact member that isconfigured to contact the eye and maintain a position of the eye.

In some embodiments, a method is described, of radiation therapy of aneye, including, for an ocular disease having an associated dose ofradiation useful therapeutically to treat that disease, providing adistance from an x-ray source located outside the eye, that is todeliver the dose of radiation via an x-ray beam, to a target of eyetissue afflicted by the disease; and based on the distance of the targetfrom the radiation source, outputting to an output module an energylevel required to achieve the dose of radiation in the x-ray beamemitted from the radiation source to the target, the target beingseparated from the radiation source by the distance; wherein the energylevel is dependent on the distance of the target from the radiationsource.

Some embodiments describe a method, for treating diseased tissue withradiation, including selecting, based on a first disease in a patient tobe treated, an energy level in a radiation beam to be emitted from aradiotherapy system, the radiation beam delivering substantially anestimated dose of radiation; wherein the first disease to be treated isone of a plurality of diseases; and wherein each of the plurality ofdiseases requires a different energy level to achieve a therapeutic doseof radiation for that disease than the energy level required to achievethe therapeutic dose of radiation for another of the plurality ofdiseases; and outputting to an output module an indication of theselected energy level.

In some embodiments, the first disease affects an eye of the patient andthe radiation beam is emitted toward the eye. In some embodiments, thefirst disease comprises macular degeneration of an eye of the patient.In some embodiments, the first disease comprises a pterygium of an eyeof the patient. In some embodiments, the first disease comprises atleast one of an ocular tumor, glaucoma, and premalignant lesions.

In some embodiments, described is a system, for treating diseased tissuewith radiation, including a processing module that receives an input,the input comprising a selection, based on a first disease in a patientto be treated, an energy level in a radiation beam to be emitted from aradiotherapy system, the radiation beam delivering substantially anestimated dose of radiation; wherein the first disease to be treated isone of a plurality of diseases; and wherein each of the plurality ofdiseases requires a different energy level to achieve a therapeutic doseof radiation for that disease than the energy level required to achievethe therapeutic dose of radiation for another of the plurality ofdiseases; and wherein, based on the input, the processing module outputsto an output module an indication of the selected energy level.

Some embodiments describe a method, for treating diseased tissue withradiation, including selecting, based on a first disease in a patient tobe treated, an energy level in a radiation beam to be emitted from aradiotherapy system, the radiation beam delivering substantially anestimated dose of radiation; wherein the first disease to be treated isone of a plurality of diseases; and wherein each of the plurality ofdiseases requires a different at least one of an energy level, a beamsize, and a surface-to-depth ratio to achieve a therapeutic dose ofradiation for that disease than the energy level required to achieve thetherapeutic dose of radiation for another of the plurality of diseases;and outputting to an output module an indication of the selected energylevel.

In some embodiments, a radiotherapy system is described, for treatingdiseased eye tissue, including a collimator that collimates a radiationbeam, emitted from a radiation source, to a cross-sectional width of theradiation beam to no more than about 6 mm; wherein the collimatordefines a first axis that the radiation beam follows when the radiationbeam is emitted; and a light guide that emits a light beam along asecond axis that is aligned with the first axis defined by thecollimator, the light beam providing an indication of the first axis.

In some embodiments, the light beam comprises a laser. In someembodiments, the first axis of the collimator and the second axis of thelight guide are collinear. In some embodiments, the light guide isinsertable into the eye to visualize the radiotherapy target and guidedelivery of the collinear x-ray beam from the radiotherapy system. Insome embodiments, the system further includes a cannula, into which thelight guide is insertable. In some embodiments, the cannula isconfigured to be fixed on a surface of an eye.

Some embodiments describe a system, for treating an eye with radiation,including a radiation source that emits radiation and a collimator thatcollimates the emitted radiation into a beam; an alignment system thataligns the beam with an axis traversing the eye; and a gating mechanismthat reduces radiation emission from the radiation source when the beamis not aligned with the axis.

Some embodiments further include an image detection system that detectsat least one of a fundus, a limbus, a cornea, and a reflection off asurface of the eye. In some embodiments, when the image detection systemdetects a threshold movement of the eye, the gating mechanism reducesradiation emission from the radiation source.

In some embodiments a system is described, for treating an eye withradiation, including a radiation source that emits radiation during atreatment session and that collimates the emitted radiation into acollimated beam having a cross-section dimension of less than about 6mm; and an eye mapping module that repeatedly maps locations ofstructures of an eye to a coordinate system during the treatmentsession.

Some embodiments further comprising a radiation source mover that movesthe radiation source relative to the eye to direct the emitted radiationtoward an eye structure. In some embodiments, the radiation source isconfigured to be stationary relative to a position of the eye during thetreatment session. In some embodiments, the system further includes asystem shut-off that reduces or ceases emission of radiation when an eyestructure is not in a path of the collimated beam. Some embodimentsfurther include a holder to substantially hold the eye such that an eyestructure is in a path of the collimated beam.

In some embodiments, a planning system is described, for delivery ofradiation to an eye, including a processing module that receives aninput comprising a biometric parameter of the eye; and wherein, based onthe biometric parameter, the processing module outputs to anelectromotive system a direction for an x-ray beam to be emitted ontothe sclera of the eye. In some embodiments, the biometric parametercomprises at least one of an ocular axial length, an anterior chamberdepth, a corneal thickness, and a corneal diameter.

In some embodiments, a system, for treating a target tissue with x-rayradiation, is described that includes a radiation source that emitsx-rays, the x-rays having an energy between about 1 KeV and about 300KeV; a collimator that collimates the emitted x-rays into an x-ray beam,the collimator having an inner cross-sectional dimension, the x-ray beamhaving a dose distribution at a beam spot in a plane at the targettissue, such that a dose of the x-ray beam at a region within the planeis less than about 20% of the dose at a centroid of the beam spot;wherein the region is located at a distance, away from the centroid ofthe beam spot, equal to about 70% of the inner cross-sectionaldimension; an alignment system that aligns the x-ray beam with an axistraversing the target tissue and that positions the radiation sourcewithin about 50 cm from the target tissue; and a processing module thatreceives an input comprising a parameter of the target tissue and that,based on the parameter, outputs to the alignment system a direction forthe x-ray beam to be emitted toward the target tissue.

In some embodiments, the alignment system is configured to align thex-ray beam repeatedly during a treatment session. In some embodiments,the parameter comprises a location of a fiducial marker that providesindication of a location of the target tissue.

Some embodiments described herein provide a system, for treating atarget tissue with radiation, including a radiation source that emitsx-ray radiation during a treatment session and that collimates theemitted x-ray radiation into a x-ray beam having a cross-sectionaldimension of less than about 6 mm as the beam exits the collimator; amapping module that repeatedly maps a location of the target tissue to acoordinate system during the treatment session; a movement module thatdirects the emitted x-ray radiation along a trajectory that is based, atleast in part, on at least one mapped location of the coordinate system;and a targeting module that emits a target light that indicates anapproximate center of a beam spot of the x-ray beam.

In some embodiments, the system further includes a radiation sourcemover that moves the radiation source relative to the target tissue todirect the emitted x-ray radiation toward the target tissue. In someembodiments, the radiation source is configured to be stationaryrelative to a position of the target tissue during the treatmentsession. In some embodiments, the system further includes a systemshut-off that reduces or ceases emission of radiation when the targettissue is not in a path of the collimated beam. In some embodiments, thetarget light comprises laser light.

In some embodiments, a method, of applying x-ray radiation to targettissue, is described including obtaining imaging data indicative of atarget tissue; identifying, based on the imaging data, a location of thetarget tissue; repeatedly mapping the location of the target tissue inthe coordinate system, thereby producing mapped locations of the targettissue in the coordinate system; positioning, based on the mappedlocations of the target tissue in the coordinate system, an x-raycollimator that directs an x-ray beam to the target tissue; and emittingthe x-ray beam from the collimator to the target tissue, the x-ray beamhaving an energy of from about 1 KeV to about 500 KeV; wherein the x-raybeam has a dose distribution at a beam spot in a plane at the targettissue, such that a dose of the x-ray beam at a region within the planeand outside the beam spot is less than about 20% of a dose at a centroidof the beam spot.

In some embodiments, the method further comprising making an incision intissue overlying the target tissue, prior to emitting the x-ray beamtoward the target tissue. In some embodiments, positioning the x-raycollimator further comprises placing a probe at or adjacent the targettissue. In some embodiments, the target tissue is located in a head of apatient. In some embodiments, the target tissue is located in thevasculature of a patient. In some embodiments, the target tissuecomprises peripheral vasculature. In some embodiments, the target tissueis located in the heart of a patient. In some embodiments, the targettissue is located in the gastrointestinal tract of a patient. In someembodiments, the target tissue comprises the colon or rectum of apatient. In some embodiments, a tumor comprises the target tissue. Insome embodiments, the target tissue is located in a breast of a patient.In some embodiments, the target tissue comprises musculoskeletal tissue.In some embodiments, the target tissue comprises at least one of theliver and the spleen of a patient. In some embodiments, the beam spothas a cross-sectional dimension smaller than about 1 mm. In someembodiments, the target tissue the beam spot has a diameter of betweenabout 1 mm and about 5 mm. In some embodiments, the x-ray beam comprisesalternating regions of higher intensity and lower intensity. In someembodiments, wherein the method further includes making an incision intissue overlying the target tissue, prior to emitting the x-ray beamtoward the target tissue. In some embodiments, the method furtherincludes positioning the target tissue in or on a holding module,wherein the holding module holds the target tissue substantiallystationarily while the location of the target tissue is mapped in thecoordinate system.

For purposes of summarizing the disclosure, certain aspects, advantages,and novel features of the disclosure have been described herein. It isto be understood that not necessarily all such advantages may beachieved in accordance with any particular embodiment of the disclosure.Thus, the disclosure may be embodied or carried out in a manner thatachieves or optimizes one advantage or group of advantages as taughtherein without necessarily achieving other advantages as may be taughtor suggested herein.

BRIEF DESCRIPTION OF THE DRAWINGS

A general architecture that implements the various features of thedisclosure will now be described with reference to the drawings. Thedrawings and the associated descriptions are provided to illustrateembodiments of the disclosure and not to limit the scope of thedisclosure. Throughout the drawings, reference numbers are reused toindicate correspondence between referenced elements.

FIG. 1A illustrates a side view of embodiments of a system for treatingthe eye using radiotherapy.

FIG. 1B is a schematic format of embodiments of a radiotherapy treatmentsystem.

FIG. 1C is a schematic of the eye.

FIGS. 1D and 1E depict embodiments of a radiotherapy system whichcommunicates with a lens on the eye.

FIG. 1F depicts an x-ray radiation spectrum.

FIG. 1G depicts an interface between the eye and the radiotherapydevice.

FIG. 1H depicts a mountable holder for the interface.

FIGS. 1I-1J depict schematic representations of methods used to align aradiotherapy device with a lens interface.

FIG. 1K depicts a radiotherapy system with an alignment system, whichincludes a lens interface.

FIG. 2A illustrates a side schematic view of embodiments of aradiotherapy system illustrating some system components of FIGS. 1A-1B.

FIGS. 2B′-2B″″ illustrate several embodiments of various collimators.

FIG. 2C illustrates embodiments of a radiotherapy system targeting alocation within an eye for treatment.

FIG. 2D illustrates some embodiments of a radiotherapy system targetinga location within an eye for treatment.

FIG. 2E illustrates a schematic view of a radiotherapy system and amethod of clinical application of the system.

FIG. 2F depicts a procedural scenario for determining eye biometry andusing it with systems described herein.

FIG. 2G depicts a schematic arrangement of embodiments of a radiotherapysystem and alignment system.

FIG. 2H depicts a schematic arrangement of embodiments that can be usedto align a radiotherapy system with a visual axis of an eye.

FIGS. 3A and 3B depicts embodiments of a subsystem of a radiotherapycontrol module.

FIG. 4 illustrates a side view of an eye wherein eye location is trackedaccording to methods described herein.

FIG. 5 illustrates a representative geometric model of the eye used formodeling purposes.

FIG. 6 illustrates representative beam angles with respect to ananterior surface and geometric axis of the eye.

FIGS. 7A-7F illustrate representative simulations of radiation beamstraveling through an eye to reach a retina of the eye and a dose profilefor a target tissue.

FIG. 8 depicts results of Monte Carlo simulations performed to analyzethe effect of different energies and doses on the structures of an eye.

FIG. 9 depicts results of Monte Carlo simulations performed to analyzethe effect of various treatment regimes on the various structures of theeye.

FIG. 10 depicts experimental results of thin x-ray beams travelingthrough a human eye to validate a Monte Carlo simulation model.

FIGS. 11A ¹-11B depict results of thin x-ray beams penetrating throughan eye model.

FIGS. 11C-11G depict embodiments of a treatment plan based on theoreticand experimental data.

FIGS. 11H-11I depict images of radiation beams, in which orthovoltageradiation beams as described herein are compared to other radiationbeams.

FIG. 11J depicts results of an experiment in which three beams werefocused on the back of an eye using a robotic system.

FIGS. 12A-12B depict embodiments of robotic systems, as describedherein.

FIG. 12C depicts embodiments of a treatment planning process inaccordance with embodiments described herein.

FIG. 12D depicts embodiments in which the radiotherapy device is alignedto a needle placed partially through the sclera.

FIG. 13 depicts embodiments of a radiotherapy system in a surgicaltheater.

FIGS. 14A-14B depict embodiments of radiotherapy applied to a breast.

FIG. 15 depicts embodiments of radiotherapy applied in connection with aneurosurgical procedure.

FIGS. 16A-16B depict embodiments of radiotherapy applied to musculoskeletal tissue.

FIGS. 17A-17B depict embodiments of radiotherapy applied to thevasculature.

FIG. 18 depicts embodiments of radiotherapy applied to the abdomen.

FIG. 19 depicts embodiments of radiotherapy applied to thegastrointestinal tract.

FIG. 20 depicts embodiments of radiotherapy applied in connection withthe vasculature.

FIG. 21 depicts embodiments of applications of radiotherapy systemsdescribed herein.

FIG. 22 depicts embodiments of radiotherapy in connection with a drugevaluation system.

DETAILED DESCRIPTION

Embodiments described herein include systems and methods for treating ahuman eye with radiotherapy. Some embodiments described below relate tosystems and methods for treating macular degeneration of the eye usingradiotherapy. For example, in some embodiments, systems and methods aredescribed for use of radiotherapy on select portions of the retina toimpede or reduce neovascularization of the retina. Some embodimentsdescribed herein also relate to systems and methods for treatingglaucoma or controlling wound healing using radiotherapy. For example,embodiments of systems and methods are described for use of radiotherapyon tissue in the anterior chamber following glaucoma surgery, such astrabeculoplasty, trabeculotomy, canaloplasty, and laser iridotomy, toreduce the likelihood of postoperative complications. In otherembodiments, systems and methods are described to use radiotherapy totreat drusen, inflammatory deposits in the retina that are thought tolead to vision loss in macular degeneration. Localized treatment ofdrusen and the surrounding inflammation may prevent the progression ofdry and/or wet AMD.

In some embodiments, laser therapy is applied to drusen in combination(adjuvant therapy) with co-localized x-ray radiation to substantiallythe same location where the laser is incident upon the retina; the lasercan create a localized heating effect which can facilitate radiationtreatment, or the laser can ablate a region, or laser spot, while theradiation can prevent further scarring around the region. Suchcombination therapy can enhance the efficacy of each therapyindividually. Similarly, adjuvant therapies can include x-rayradiotherapy in combination with one or more pharmaceuticals or otherradiotherapy-enhancing drugs or chemical entities. In some embodiments,x-ray therapy is combined with invasive surgery such as a vitrectomy,cataract removal, trabeculoplasty, trabeculectomy, laserphotocoagulation, and other surgeries.

Radiation, as used herein, is a broad term and is intended to have itsordinary meaning, which includes, without limitation, at least anyphotonic-based electromagnetic radiation which covers the range fromgamma radiation to radiowaves and includes x-ray, ultraviolet, visible,infrared, microwave, and radiowave energies. Therefore, planned anddirected radiotherapy can be applied to an eye with energies in any ofthese wavelength ranges.

Radiotherapy, as used in this disclosure, is a broad term and isintended to have its ordinary meaning, which includes, withoutlimitation, at least any type of clinical therapy that treats a diseaseby delivery of energy through electromagnetic radiation. X-ray radiationgenerally refers to photons with wavelengths below about 10 nm down toabout 0.01 nm. Gamma rays refer to electromagnetic waves withwavelengths below about 0.01 nm. Ultraviolet radiation refers to photonswith wavelengths from about 10 nm to about 400 nm. Visible radiationrefers to photons with wavelengths from about 400 nm to about 700 nm.Photons with wavelengths above 700 nm are generally in the infraredradiation regions. Within the x-ray regime of electromagnetic radiation,low energy x-rays can be referred to as orthovoltage. While the exactphoton energies included within the definition of orthovoltage varies,for the disclosure herein, orthovoltage refers at least to x-ray photonswith energies from about 20 keV to about 500 keV.

As used herein, the term “global coordinate system” can refer, in part,to a physical world of a machine or room. The global coordinate systemis generally a system relating a machine, such as a computer or otheroperating device, to the physical world or room that is used by themachine, using, for example, a set of virtual points or lines thatassist in relating corresponding structures between the machine andphysical world. The global coordinate system can be used, for example,to move a machine, components of a machine, or other things from a firstposition to a second position. The global coordinate system can also beused, for example, to identify the location of a first item with respectto a second item. In some embodiments, the global coordinate system isbased on a one-dimensional environment. In some embodiments, the globalcoordinate system is based on a two-dimensional environment, and in someembodiments, the global coordinate system is based on three or moredimensional environments.

Kerma, as used herein, refers to the energy released (or absorbed) pervolume of air when the air is hit with an x-ray beam. The unit ofmeasure for Kerma is Gy. Air-kerma rate is the Kerma (in Gy) absorbed inair per unit time. Similarly, “tissue kerma” rate is the radiationabsorbed in tissue per unit time. Kerma is generally agnostic to thewavelength of radiation, as it incorporates all wavelengths into itsjoules reading.

As used herein, the term “radiation dose” is a broad term and isgenerally meant to include, without limitation, absorbed energy per unitmass of tissue. One example of a measure of radiation dose is the Gray,which is equal to 1 joule per kilogram, which generally also equals 100rad. For example, as used herein in some embodiments, a radiation dosemay be the amount of radiation, or absorbed energy per unit mass oftissue, that is received or delivered during a particular period oftime. For example, a radiation dose may be the amount of absorbed energyper unit mass of tissue during a treatment process, session, orprocedure.

As used herein, the term “trajectory” is a broad term and is generallymeant to include, without limitation, a general path, orientation,angle, or direction of travel. For example, as used herein in someembodiments, the trajectory of a light beam can include the actual orplanned path of the light beam. In some embodiments, the trajectory of alight beam can be determined by an orientation of a light source thatemits the light beam, and the trajectory can, in some embodiments, bemeasured, such as by an angle, or determined as with respect to areference, such as an axis or plane.

As used herein, the term “aligned” is a broad term and is generallymeant to include, without limitation, having a fixed angularrelationship between zero and 180 degrees. For example, as used herein,two light beams or x-ray beams can be aligned if they are collinear, areoriented with respect to each other at a fixed angle, or have anotherfixed relationship. In some embodiments, the angle between aligned lightbeams or x-ray beams can range from about zero degrees to about 360degrees, and can include about 90 degrees, about 180 degrees, and about270 degrees.

“Treatment axis,” as used herein, is a broad term and is generally meantto include, without limitation, an axis of an organ in relation with theradiotherapy device. For example, in some embodiments, the axis of theorgan is related, such as by an angle, to an axis of the radiotherapydevice. In some embodiments, the intersection of the organ axis and theradiotherapy device is used to define the target for the radiotherapybeam.

As used herein, the term “treatment session” is a broad term, and isgenerally meant to include, without limitation, a single or a pluralityof administrations of at least one of heat therapy, radiation therapy,or other therapeutic treatment of target tissue. For example, in someembodiments, a treatment session can include a single administration ofx-ray beams to the eye. In some embodiments a treatment session caninclude a plurality of administrations of x-ray beams and laserradiation to the a patient's eye. In some embodiments, a treatmentsession is limited to, for example, a single visit by a patient to aclinic for treatment, and in some embodiments, a treatment session canextend over a plurality of visits by a patient to the clinic. In someembodiments, a treatment session can include a single procedure ofadministering radiotherapy, and in some embodiments, a treatment sessioncan include a plurality of procedures following different protocols foreach procedure. In some embodiments, a treatment session may be limitedto about a single day, and in some embodiments, a treatment session canbe about 2 days, about 3 days, about 5 days, about 1 week, about 10days, about 2 weeks, about 3 weeks, about 1 month, about 6 weeks, about2 months, about 3 months, about 6 months, about 1 year, or longer. Asused herein, the term “treatment period” is a broad term, and isgenerally meant to include, without limitation, any single or pluralityof administrations of radiotherapy or related therapeutic treatment oftissue, and can include a single or a plurality of treatment sessions.

As used herein, the term “orders of magnitude” is a broad term and isgenerally meant to include, without limitation, a class of scale ormagnitude of any amount, where each class contains values of a ratiorelated to the class preceding it. For example, in some embodiments, theratio relating each class may be 10. In these embodiments, one order ofmagnitude is a magnitude based on a multiple of 10, two orders ofmagnitude is based on two multiples of 10, or 100, and three orders ofmagnitude is based on three multiples of 10, or 1000.

In some embodiments, the radiotherapy system is configured to producebeams of radiation for radiotherapy. The beams can be collimated toproduce beams of different size or cross-sectional shape. The beam shapeis generally defined by the last collimator opening in the x-ray path;with two collimators in the beam path, the secondary collimator is thelast collimator in the beam path and can be called the “shapingcollimator.” The first collimator may be called the primary collimatorbecause it is the first decrement in x-ray power and can be the largestdecrement of the collimators; the second collimator can generally setthe final shape of the x-ray beam. As an example, if the last collimatoropening is a square, then the beam shape is a square as well. If thelast collimator opening is circular, then the beam is circular. If thelast collimator has multiple holes then the beam will have multipleholes of any shape (areas of radiation and no or limited radiation) init as it reaches the target. In some embodiments, there is onecollimator which serves as the primary collimator as well as the beamshaping collimator.

The penumbra refers to the spread in dose outside an area of the lastcollimator and the beam shape and size set by that collimator, typicallymeasured at some distance from the last collimator. Penumbra, as usedherein, is a broad term and has its ordinary meaning, which is meant toinclude, without limitation, the percentage of radiation outside thearea of the last collimator when the x-ray beam reaches a first surfaceof tissue or an internal target tissue, whichever is being referencedwith respect to the penumbra. For example, the penumbra can include thepercentage of radiation outside the area of the last collimator when thex-ray beam reaches the surface of the eye or when the x-ray beam reachesthe retina of the eye. The penumbra can also refer to the relationshipof a cross-sectional dimension or area of the collimator and across-sectional dimension of radiation incident upon the target site.For example, if the collimator produces a beam having a circular shape,the diameter of the collimator can be compared with the greater diameterof the beam at the treatment site. In this context, the penumbra canrefer to the percentage of increased diameter of the beam at thetreatment site in comparison to the originating diameter at thecollimator.

The penumbra can incorporate divergence of the beam as well as scatterof the beam as a result of passage through air and tissue. Although notmeant to be limiting, penumbra is used in some embodiments that followas the linear distance from the primary beam size where the radiationlevel drops below 20% of the radiation in the primary beam sizeincluding both scatter and beam divergence. As an example, if a beamdiameter determined by a collimator is 5 mm at the exit of thecollimator and the diameter at the tissue target where the radiationdosage is 20% of the dose over the 5 mm beam diameter (at the tissue) is6 mm, then the penumbra is 0.5/3.0 mm (radius) or 16%.

Ideally, the size of the beam incident upon target tissue is the samesize as the last collimator to which the x-ray beam is exposed; that is,the penumbra is ideally zero. In reality, a penumbra of zero isdifficult to achieve when the collimator is any distance from the targetbecause of beam divergence. However, the penumbra can be optimized, forexample, by the shape of the collimator, the material of the collimator,the processing of the collimator material, the position of the anode ofthe x-ray tube, the position of the collimator relative to the anode ofthe x-ray tube and the tissue target, and the relative sizing of thecollimator with respect to the x-ray source. In some embodiments of thesystems and methods provided herein, the penumbra percentage at theentry point to the tissue (e.g., the eye) is less than about 10%. Insome embodiments, the penumbra percentage at the entry point is lessthan about 5%, and in some embodiments, the penumbra percentage at theentry point is less than about 1%.

The penumbra can also refer to the percentage of radiation outside thezone of the shaping collimator at a target region. For example, inapplications to the eye, the penumbra can refer to the percentage ofradiation outside the zone of the shaping collimator at the maculadefined above. In some embodiments, the penumbra at the macula is lessthan about 40%; in some embodiments, the penumbra at the macula is lessthan about 20%; in some embodiments, the penumbra at the macula is lessthan about 10%; and in some embodiments, the penumbra at the macular isless than about 5%. The penumbra can be a factor or parameter that isincorporated into a treatment plan; for example, predictive knowledge ofthe penumbra can be utilized to plan the treatment. In one example, afinely collimated beam (e.g., having a 4-mm diameter at the exit of thelast collimator) is applied to the sclera. The beam at the retina can be5 mm (25% penumbra) or 6 mm (50% penumbra) diameter, which can besufficient for coverage of a lesion. With this method, the structures ofthe anterior eye are minimally irradiated while the lesion at the retinais fully covered. In this embodiment, divergence of the x-ray beam isutilized for minimizing the size of exposed tissue in the front of theeye without sacrificing a therapeutic dose to the retina.

A related definition is that of “isodose fall-off” which refers to thedose fall-off; it is a dose map of the area of interest. The isodosefall-off can be measured in Gy/mm, in which mm represents a lineardistance from a point of interest.

Divergence angle is highly predictable for photons given the geometry ofthe source and can be calculated independently of scatter and the otherphysics which are factored into and contemplated by Monte Carlosimulations. In most instances, the x-ray source is not an idealizedpoint source and has a finite volume. This non-idealized case entersinto consideration in the design of the collimators in the beam path, asthe collimators may be designed differently for a non-idealized x-raysource than for an idealized point source. For example, the x-ray sourcemay have a source which is a square or a rectangle or an ellipse. Thegreatest diameter of the source may be about 0.5 mm, about 1.0 mm, about2.0 mm, about 3.0 mm, about 4.0 mm, or about 5.0 mm. In someembodiments, the greatest diameter of the source may further beadjustable depending on the structure being treated.

Photons with shorter wavelengths correspond to radiation with higherenergies. The higher-energy range of x-rays is generally in the MeVrange and is generally referred to gamma x-rays, independent of how theradiation was generated. X-ray photons with relatively shorterwavelengths are referred to as orthovoltage x-rays. Higher energyradiation with shorter wavelengths corresponds to deeper penetrationinto target tissue, which is the reason that most applications using MeVenergies require extensive shielding of the patient and surroundings. Insome embodiments of this disclosure, x-rays typically used fordiagnostic purposes, or low energy orthovoltage x-ray sources, can beused for therapy of ocular diseases and/or disorders which arerelatively superficial in the patient such as breast, intra-operativeradiation application, skin cancers, and other disorders such asperipheral vascular disease, implants, etc. X-rays typically used fordiagnosis can be used for therapy by tightly collimating the x-ray beaminto a thin beam of x-ray photons and directing the beam to thesuperficial region to be treated. If the disorder is deeper than severalcentimeters inside the body, then higher energy sources (e.g., MeV) maybe preferred to enhance penetration of energy to the disorders. It isdifficult to collimate MeV x-ray beams to small diameters with smallpenumbras because their very high speed photons cause secondaryinteractions with tissue including generation of secondary x-rays andother radiations. X-rays with energies lower than 500 keV and even lowerthan 200 keV can more appropriately be collimated to very smalldiameters.

“Laser” energy is also composed of photons of different energies rangingfrom short wavelengths, such as ultraviolet radiation, up to longwavelengths, such as infrared radiation. Laser refers more to thedelivery mechanism than to the specific wavelength of radiation. Laserlight is considered “coherent” in that the photons travel in phase withone another and with little divergence. Laser light is also collimatedin that it travels with relatively little divergence as is proceeds inspace. Light can be collimated without being coherent (in phase) andwithout being a laser; for example, lenses can be used to collimatenon-x-ray light. X-ray light is typically collimated with the use ofnon-lens collimators, the penumbra defining the degree of successfulcollimation. Laser pointers are typically visualization tools, whereaslarger, higher-flux lasers are utilized for therapeutic applications. Insome embodiments of the systems and methods described herein, optics canbe used, such as lenses or mirrors, and in some embodiments, there areno intervening optical elements, although collimators may be used.

The two eye chambers are the anterior and posterior chambers. Theanterior chamber includes, among other things, the lens, theconjunctiva, the cornea, the sclera, the trabecular apparatus, theciliary bodies, muscles, and processes, and the iris. The posteriorchamber includes, among other things, the vitreous humor, the retina,and the optic nerve.

“Ocular diseases,” as used in this disclosure, is a broad term and isintended to have its ordinary meaning, which includes, withoutlimitation, at least diseases of the anterior eye (e.g., glaucoma,presbyopia, cataracts, dry eye, conjunctivitis) as well as diseases ofthe posterior eye (e.g., retinopathies, age related maculardegeneration, diabetic macular degeneration, and choroidal melanoma).

Drusen are hyaline deposits in Bruch's membrane beneath the retina. Thedeposits are caused by, or are at least markers of inflammatoryprocesses. They are present in a large percentage of patients over theage of 70. Although causality is not known, drusen are associated withmarkers of the location where inflammation is occurring and whereneovascularization has a high likelihood of occurring in the future;these are regions of so called “vulnerable retina.” Therefore, applyinginflammation-reducing radiation to the region may be beneficial to thepatient, as described herein.

Radiation therapy has historically been marginally successful intreating disorders of the eye; for example, in a recent Cochranemeta-analysis review (Signanavanel et. al. Radiotherapy for neovascularage-related macular degeneration, The Cochrane Database, Issue 4, 2006,the entirety of which is incorporated by reference), the authorsdiscussed the merits of radiation therapy for AMD. Among their generalconclusions were the following: ophthalmologists were reluctant to referpatients to the radiation oncologists; it was difficult to localize theradiation from the radiation source because specific methods were notused for the clinical protocol; and fractionation schemes and dosing wasnot standardized (this is described in further detail below and in thefigures). The embodiments described in this disclosure provide forsystems and methods that can be performed by the ophthalmologist,without referral to a radiation oncology clinic, that can localize theradiation source through apparatus and protocols specific to theclinical treatments, and fractionation schemes that provide standardizeddosing.

Brachytherapy appears to have a highly beneficial effect at least whencombined with pharmaceutical therapy as an adjuvant therapy.Brachytherapy provides the radiation dose to the region to be treatedand delivers the dose at a high rate. However, brachytherapy isdifficult to control as far as a treatment plan (e.g., the surgeon canhold the probe in a variety of positions for any given patient), and thebrachytherapy source typically cannot be turned off (e.g., strontium hasa 29 year half-life).

Radiotherapy System

The Portable Orthovoltage Radiotherapy Treatment system (PORT) 10 inFIG. 1A can be configured to deliver anywhere from about 1 Gy to about40 Gy during a treatment period, or from about 10 Gy to about 20 Gyduring a treatment period, to regions of the eye including, but notlimited to, the retina, sclera, macula, optic nerve, the capsular bag ofthe crystalline or artificial lens, ciliary muscles, lens, cornea, canalof schlemm, choroid, and conjunctiva. In some embodiments, the systemcan be configured to deliver from about 15 Gy to about 25 Gy during atreatment period. In some embodiments, the system 10 is capable ofdelivering x-ray therapy in any fractionation scheme (e.g., about 1 Gyper day, about 5 Gy per day, about 10 Gy per month, or about 25 Gy peryear), as the treatment planning system can retain in memory and recallwhich regions had been treated based on the unique patient anatomicaland disease features. These features and previous treatments are storedin the treatment database for future reference.

The system can also deliver different photon energies depending on thedegree of disease or the region of the eye being treated. For example,the x-ray generation tube can deliver photons with photon energiesranging from about 20 keV to about 40 keV, to about 60 keV, or to about100 keV. It may be desirable to use photons with photon energies rangingfrom about 20 keV to about 50 keV for structures in the anterior portionof the eye because photons with these photon energies will penetrateless. It may be desirable to utilize photons with photon energiesranging from about 60 keV to about 100 keV or greater for structures inthe posterior region of the eye for greater penetration to the retina.In some embodiments, the x-ray generation tube can emit photons withphoton energies from about 10 keV to about 500 keV, from about 25 keV toabout 100 keV, from about 25 keV to about 150 keV, from about 40 keV toabout 100 keV, or any combination of ranges described above or herein.In some embodiments, selection of the photon energy can be based ondiagnostic calculations, which can include a model of the eye createdfrom anatomic data taken from the actual eye of the patient to betreated. The treating medical practitioner can choose the beam energiesbased on the disease and then set the machine to the desired energylevel. In some embodiments, the system can receive input from themedical practitioner relating to the type of disease, and the energylevel can be preset, which can also be subject to modification by themedical practitioner.

Although several embodiments herein are described with respect to ocularapplications, PORT can be applied to any superficial body structurewithin reach of orthovoltage x-rays or to structures accessible duringsurgical procedures. For example, in regions such as the breast, it maybe desirable to use x-rays with energies greater than about 40 keV butless than about 200 keV to reach the structures of interest. Otherstructures of interest include, for example, skin lesions, faciallesions, mucosal lesions of the head and neck, nails, muscles, softtissues, anorectal regions, prostate, genital regions, joints, tendons,muscles, and the urogenital tract.

PORT can be applied to specific structures within the eye, while sparingother tissues, because PORT's imaging systems, modeling systems, andfinely-tunable collimators can provide precisely directed x-ray beamsthat can be targeted on specific structures within the eye with smallpenumbras (for example, about 1 mm to about 5 mm beams with less thanabout 10-20% penumbra). PORT therapy is also based on individualized,biometric representations of the eye which allows a personalizedtreatment plan to be created for every patient.

As described above, orthovoltage generators, or other low energy x-raygenerators, allow for the system to be placed in a room withoutrequiring thick protective walls, special shielding apparatus, orspecial controls which would be required with devices generating x-rayswith photon energies greater than about 500 keV. Orthovoltagegenerators, or other low energy x-ray generators, are also more compactthan linear accelerators, which allow the smaller generators to be movedand directed with less energy from control motors as well as with lessinternal and external shielding. The lower energy x-ray generators alsofacilitate beam collimation and directing schemes, resulting in beamshaving smaller penumbras and capable of tighter collimation. Inaddition, in a scheme where it is desired to move the x-ray source, muchless energy is used to move the source to different positions, and theentire system is scaled down in size with lower energy x-ray sources.

In some embodiments, the radiotherapy system is used to treat a widevariety of medical conditions relating to the eye. For example, thesystem may be used alone or in combination with other treatments totreat macular degeneration, diabetic retinopathy, inflammatoryretinopathies, infectious retinopathies, tumors in, around, or near theeye, glaucoma, refractive disorders, cataracts, post-surgicalinflammation of any of the structures of the eye (e.g., trabeculoplasty,trabeculectomy, intraocular lenses, glaucoma drainage tubes, cornealtransplants, infections, idiopathic inflammatory disorders, etc.),ptyrigium, dry eye, and other ocular diseases or other medicalconditions relating to the eye. The radiotherapy system also includescontrols for maximum beam energy (e.g., ranging between about 30 keV toabout 150 keV), beam angles, eye geometries, and controls to turn offthe device when the patient and/or eye move out of position.

The radiotherapy treatment system includes, in some embodiments, aradiation source, a system to control and move the source to acoordinate in three-dimensional space, an imaging system, and aninterface for a health care professional to input treatment parameters.Specifically, some embodiments of the radiotherapy system include aradiotherapy generation module or subsystem that includes the radiationsource and the power supplies to operate the source, an electromotivecontrol module or subsystem that operates to control power to the sourceas well as the directionality of the source, a coupling module thatlinks the source and control to the structures of interest (e.g., theeye), and an imaging subsystem. In some embodiments, these modules arelinked to an interface for a healthcare professional and form theunderpinnings of the treatment planning system. The terms “module” and“subsystems” can be used interchangeably in this disclosure.

FIG. 1A illustrates a side view of embodiments of a system 10 fortreating ocular diseases using radiotherapy. In some embodiments, asillustrated, the radiotherapy treatment system 10 comprises aradiotherapy generation module or subsystem 110, a radiotherapy controlmodule or subsystem 120, an interface display 130, a processing module140, a power supply 150, a head restraint 160, and an imaging module400, which can be a camera.

In some embodiments, the radiotherapy device delivers x-rays to the eye210 of a patient 220. The power supply 150 preferably resides inside thesystem 10 or adjacent the system 10 (e.g., on the floor). In someembodiments, however, the power supply 150 can reside in a differentlocation positioned away from the system 10. The power supply 150 can bephysically coupled to the x-ray generator 110 (in a monoblockconfiguration) or can be uncoupled from the x-ray generator (e.g., thex-ray source moves independently of the power supply and is connectedthrough, for example, high power cables). In some embodiments, the powersupply is a rechargeable, portable supply. In some embodiments, acooling system for the x-ray tube is also provided. The cooling systemcan be water, oil, or air convection, and the cooling system can beattached to or located a distance from the radiotherapy system 10.

Voltage can be wall voltage of about 110V or about 220V (with assistanceof a transformer) which can be used for the devices, subsystems, ormodules of the system. Currents supplied to the system to generatex-rays may be on the order of about 1 amp or lower down to about 50 mAor even about 5 mA to about 10 mA. In some embodiments, the power supplycan deliver currents up to hundreds of milliamps (e.g., about 600 mA).For example, currents ranging from about 100 mA to about 1 amp, orgreater, can be used when protocols or features of the system areconfigured to accommodate these higher current, such as, for example,when the x-ray source is a rotating anode source.

In some embodiments, what is desired of the power supply is that a highvoltage be generated to drive the electrons from the cathode in thex-ray tube to the anode of the x-ray; electron movement is performedwithin a vacuum inside the x-ray tube. The high voltage (e.g., about30,000 to about 300,000 volts or higher) may be desired to acceleratethe electrons inside the vacuum. A second current is typically used withx-ray power supplies in order to generate the electrons from a filament,the electrons are subsequently accelerated through the voltagepotential. Therefore, x-ray power supplies typically have two powersupplies in order to generate x-rays. Once generated, the electronsspeed toward the anode under the influence of the high voltagepotential; the anode is where the x-ray generating material typicallyrests (e.g., tungsten, molybdenum).

The anode is considered the radiation source, and its size and structurehas a role in penumbra determinations. For example, a point source maybe approximated by a anode with a largest diameter of equal to or lessthan about 1 mm; points sources can deliver the highest quality beamwith the tightest penumbra. Less optimal are sources with anodes greaterthan about 1 mm; for example, 2-mm, 3-mm, 4-mm, or 5-mm sources can alsobe used in connection with the embodiments described herein. However,the penumbra is typically larger than it would be with sources havingthese larger dimensions than for a source having a cross-sectiondimension that is equal to or less than about 1 mm. The anode is also amajor determinant of the x-ray flux. The heat generated by the anode isthe major limiting factor in the ultimate flux which can be achieved bythe x-ray source. To the extent the anode can be cooled, the x-ray fluxcan be increased accordingly. This is part of the trade-off in penumbra;larger anodes can tolerate larger currents due to their larger thermalmass. X-ray output is related to current so higher current for a lowertemperature allows a greater x-ray flux. In some embodiments, rotatinganode sources are used so that the anode is “cooled” by virtue of theanode being moved to different points with time.

Once the electrons strike the x-ray generating material, x-rays aregenerated. An absorbing metal (e.g., aluminum, lead, or tungsten) withinthe casing of the system will absorb much of the generated x-rays whichhave been scattered from the source 110. The x-rays, which arepre-planned to escape, are emitted from the source and travel into acollimator (e.g., a primary or secondary collimator) and optionallythrough a filter (e.g., an aluminum filter). The collimator is intendedto direct the x-rays toward the patient 220. Notably, as describedherein, collimators can be designed and manufactured so as to minimizepenumbra formation and scatter and to optimize the shape and/ordirection of the x-ray beam. The power supply is preferably connected tothe x-ray source by a high-power cable that can be highly insulated toreduce power leakage.

The collimator can be one or more collimators (e.g., as illustrated inFIG. 2A, a primary collimator 1030 and a secondary collimator 1040, andeven a third collimator 1052). In some embodiments, a secondary(shaping) collimator is placed close to the eye 1300 (e.g., within 10cm) of the patient, and the primary collimator 1030 is placed close tothe source 1070. This type of configuration can decrease the penumbragenerated by the source 1070 on the ocular structures of the eye 1300.The source can include filtration or the collimator can includefiltration.

In some embodiments, collimators are specialized apertures. Theapertures can be adjustable; for example, the aperture can be adjustablefrom about 1.0 cm to about 0.5 mm or below 0.5 cm to about 0.01 cm. Insome embodiments, the aperture is adjustable (e.g., automatically ormanually by the operator of the machine) between about 0.5 mm and about7.0 mm. In some embodiments, the collimator is constructed fromtungsten, lead, aluminum, or another heavy metal. In some embodiments,the collimator has a cylindrical shape for the radiation to passthrough; in some embodiments, the collimator has a coned shape for theradiation to pass through. In some embodiments, the collimator aperturehas a rounded shape. In certain embodiments, the collimator has acurvilinear shape for the x-ray to pass through. The collimator can beshaped to accommodate the distribution of radiation desired at thetarget; for example, in some embodiments, it is desirable to avoid theoptic nerve while focusing radiation on the macular region. To avoid theoptic nerve, it may be desirable for the radiation to be directedthrough a crescent shaped collimator or another weighted distributionsuch that the optic nerve side (nasal side) of the macula receives lessdose than the temporal side of the macula.

In some embodiments, the collimator is cut using wire-EDM; in otherembodiments, the collimator path is cut and polished using a laser. Insome embodiments, the collimator has smooth contoured, cut and polishededges that reduces scattering as the radiation passes through thecollimation apparatus. In some embodiments, the collimator has a regionof thinner metal than another region so that the beam is relativelymodified but does not have a sharp contour. In other embodiments, thecollimator is not a complete aperture but is a thinning of the materialat the region where a greater amount of x-ray energy is desired. Forexample, a thickness of the filter material may vary depending on theshape or desired filtering properties of the filter material. In someembodiments, reducing a thickness of the filter material by half allowsradiation beams to pass through the portion of the reduced thickness ofthe filter material, but the radiation beams are still substantiallyblocked from passing through the portions of the filter material that donot have a reduced thickness. In some embodiments, the thickness of thefilter remains constant throughout, but materials having differentradiopacity are used. For example, a material having a higherradiopacity is used to filter the x-ray emission, and a material havinga lower radiopacity is used, for example, in the place of the apertureto permit passage of the x-rays.

In some embodiments (e.g., FIG. 2C), a light pointer 1410 (e.g., a laserbeam emitted from a source 1450) is coupled to a collimator 1405, orbehind the collimator 1405, so that the light pointer 1410 is coincidentwith an x-ray beam 1400; the light pointer 1410 can indicate theposition on a surface of an eye 1300 through which the radiation sourceenters by tracking angles of incidence 1420, 1430 of the collimator andx-ray beam. The collimator 1405 is preferably collinear with the lightsource 1450, which can act as a pointer to indicate the point on the eyethrough which the radiation enters the eye 1300. In some embodiments,the light pointer position is used to track the radiotherapy sourcevis-à-vis an image recognition system which identifies the position ofthe pointer relative to an ocular structure (e.g., the limbus) and theradiotherapy device is then moved based on the image (e.g., to a regionfurther away from or closer to the limbus of the eye). In someembodiments, the physician visualizes the position of the laser pointerrelative to the limbus and manually adjusts the x-ray source intoposition.

In some embodiments, a laser pointer 1210, illustrated in FIG. 2B′, sitson top of, or is coincident with the x-ray beam through the primary orsecondary collimator 1215. The laser pointer 1210 can be reflected off areflector 1220 that aligns the laser pointer 1210 with the collimatoropening 1216 such that the laser point 1210 strikes substantially thesame position of a surface beyond the collimator opening as does thex-ray 1200. In some embodiments, the laser pointer 1210 is aligned withthe collimator opening 1216 such that the laser point 1210 hassubstantially the same trajectory as does the x-ray beam 1200 thatpasses through the collimator opening 1216. In any case, the directionof the laser pointer 1210 and the x-ray beam 1200 are coupled to oneanother so that knowledge of the position of either is equivalent toknowledge of the position of the other beam.

The reflector 1220 can be a beam splitter, and the beam splitter can betransparent to x-ray energy 1200 or even act as a filter to create thedesired spectrum of x-ray energy. The laser pointer 1210 can emit awavelength that is detectable by the system camera 1460 (illustrated inFIG. 2C). Because the pointer 1210 is seen on the camera, the pointer1210 indicates where the radiation beam enters the eye. The pointer 1410can also serve as a visual verification that the x-ray source is poweredon and directed in the proper orientation with respect to the ocularstructure, or target tissue 1480, of interest. With a second camera inthe system, the angle of incidence of the laser pointer, and bydefinition, the x-ray beam can be determined.

At least one imaging module 400, 1460, such as a camera, is included inthe system to at least track the eye in real time. In some embodiments,the imaging module 400, 1460, or camera, images the eye with or withoutthe x-ray source tracking device (e.g., laser pointer 1210) describedabove. The camera can detect the position of the eye and relate thedirection of the x-ray and collimator system to the position of the eye.An optional display 130 directed to the operator of the radiotherapysystem on the system 10 can depict the position of the x-ray device inreal time in some embodiments.

In some embodiments (FIG. 4), the camera 2055 detects the position ofthe eye, and digitizing software is used to track the position of theeye. The eye is meant to remain within a preset position 2060, ortreatment field, which can correspond to the edges of the limbus; whenthe eye deviates from the position 2054 beyond a movement threshold, asignal 2090 can be sent to the radiation source 2000. As used herein,the term “movement threshold” is a broad term and is intended to haveits ordinary meaning, which includes, without limitation, a degree ormeasurement that the eye is able to move and remain within theparameters of treatment without shutting the radiation source 2000 off.In some embodiments, the movement threshold can be measured in radians,degrees, millimeters, inches, etc. The radiation source 2000 is turnedoff when the eye is out of position 2057 beyond the movement threshold,and the radiation source is turned on when the eye is in position 2054,or within the movement threshold. In some methods of setting themovement threshold, a treating professional delimits the edges of thelimbus 2060 and the treatment planning software then registers the edgesof the limbus 2060. If the limbus of the eye moves away 2030 from thedelimited edge limit, a signal 2090 is sent to the radiation device toshut down.

In some embodiments, a connection, or coupling, 162 extends from thesystem and contacts the eye 210 (FIGS. 1D and 1E). The connection can bea physical connection which can include an optical or othercommunication between the system and the eye in addition to a mechanicalconnection. The physical connection 162 can serve several functions. Forexample, in some embodiments, the connection 162 is a mechanicalextension which allows the position of the eye to be determined becauseit is directly applied to the cornea or sclera. It also provides forinhibition of the eye so that the patient is more inclined to becompliant with keeping their eye in one position throughout thetreatment. In addition, the eye can be moved into a pre-determinedposition, in the case, for example, when the patient's eye has beenparalyzed to perform the procedure. Finally, the physical contact withthe eye can be used to protect the corneal region using an ophthalmiclubricant underneath the physical contact device. The physicalconnection 162 from the cornea allows for positioning of the eye withrespect to the system.

The physical connection 162 to the eye from the radiotherapy system 10can contact the limbus 905 in FIG. 1E (also see 308 in FIG. 1C) aroundthe eye or can contact the cornea 915 or the sclera 925. The physicalconnection can contain a suction type device 912 which applies somefriction to the eye in order to move the eye or hold the eye in placewith some force. In certain embodiments, the connection 162 contacts thesclera when suction is applied. The physical connection 162 can dockonto a scleral lens 935 or a corneal lens which is inserted separatelyinto the eye. Any of the materials of the physical connection can betransparent to x-rays or can absorb some degree of x-ray.

The physical connection 162 can help to stabilize the eye of thepatient, reducing eye movement underneath the lens. If a lubricant isinserted inside the lens, the lens can hold a gel or lubricant toprotect the eye during the procedure. The lens can also contain throughholes which can provide the cornea with oxygen.

The physical connection 162 can be movable with respect to the remainderof the radiotherapy system; the physical connection 162 can be rigid,substantially rigid, or can contain a spring 165, which allowsflexibility in the axial or torsional direction. In some embodiments,the connection 162 is not mechanical at all but is an optical or othernon-contact method of communicating between a radiotherapy system and alens 935 positioned on the eye. The physical connection 162 can signifythe coordinate reference frame for the radiotherapy system and/or cansignal the movement of the device with respect to the eye. Connection162 can therefore assist in maintaining eye location in addition tomaintaining eye position by inhibiting movement of the patient. Physicalconnection 162 can contain radiotranmitters, a laser pointer, orfeatures which can be captured on a camera so that the eye can belocated in three-dimensional space.

In some embodiments, the physical connection 162 to the eye is dockedinto position on the eye by the physician so that it identifies thecenter of the limbus and the treatment axis through its center. Theposition of the eye can then be identified and tracked by theradiotherapy system. With knowledge of the center of the limbus incombination with the eye model, the radiotherapy system can then bedirected about the treatment axis and center of the limbus to deliverradiation to the retina.

In some embodiments, the physical connection 162 can include aradiotherapy coupling device 945 (FIG. 1G). The coupling device 945 hasan ocular surface 960, which can include, for example, a scleral lensand a radiotherapy coupling surface 950. The ocular surface 960 cancover the cornea and contact the cornea or it can cover the cornea, onlycontacting the sclera. In some embodiments, the ocular surface 960 cancover and contact both the cornea and the sclera. The ocular surface 960can be a lens in some embodiments, and in some embodiments, the surface960 can be a substantially transparent window with little or norefraction. The ocular surface 960 can be used to retain ocular gel orit can be a shell with a hole in the center. The ocular surface 960 canbe customized for an individual patient using imaging modalities, suchas for example, an IOL master, optical coherence tomography (OCT),corneal surface mapping, MRI, CT scan, and ultrasound. The ocularsurface 960 can be flexible or rigid or a composite. Flange 970 canfunction to hold the eyelids apart or can serve as a fiducial for theradiotherapy device.

Opposite the ocular surface 960 are radiotherapy coupling surfaces, orportions, 950, 955. These surfaces, individually or collectively, couplethe coupling device 945 with the radiotherapy system. While the ocularsurface 960 interfaces with the eye and structures, the radiotherapyportion 950, 955 couples the ocular surface to the radiotherapy system.The radiotherapy portion, 950, 955 can link the coupling device 945 tothe radiotherapy system in a variety of ways. For example, theradiotherapy portion 950, 955 can couple to the radiotherapy device vialaser pointer, via infrared coupling, via microwave coupling, viamechanical coupling, via reflection, or via radiofrequency transmitters.

An additional element of the coupling device 945 can be fiducial markers970 which can define geometry of the device or geometric relationshipsbetween the device 945 and the radiotherapy system. An additionalcomponent of the radiotherapy coupling device 945 in some embodiments isa lumen 985 which traverses the device and, in some embodiments, extendsto the surface of the eye. The lumen 985 can be used to pass probes 962such as may be used to determine the axial length of the eye (e.g., anA-scan). In some embodiments, the probe 962 can include a laser pointerprobe 962, which can point outward away from the eye of the patient. Theoutward pointing laser pointer can be used to determine alignment of thedevice, and therefore the eye, relative to the radiotherapy system. Insome embodiments, the laser pointer is used to align the radiotherapydevice with an axis of the eye and can be used to turn the radiotherapyon (when in position) or off (when not in position). In theseembodiments, the patient turns the device on and off, and theradiotherapy system operates when the eye is aligned with the machineand turns off when the device is not aligned with the radiotherapydevice.

In some embodiments, the probe 962 contains a mirror 964. The mirror 964can function as a beam reflector to indicate alignment or misalignmentof the radiotherapy device. For example, the mirror 964 will reflect alight such as a laser pointer or an LED. The light originates on theradiotherapy device and its reflection from the mirror 964 on thecoupling device 945 is indicative of the direction of the mirrorrelative to the radiotherapy device. The mirror can be parallel to thesurface of the cornea, and therefore, a beam perpendicular to the mirroris approximately perpendicular to the cornea. A perpendicular beam tothe cornea will travel through the optical or geometric axis of the eyeand reach the center of the posterior pole of the eye (also shown anddescribed in FIGS. 1I and 1J).

In some embodiments, the mirror is a so-called “hot mirror” or a “coldmirror” in which the mirror reflects some wavelengths and transmitsothers. For example, a “hot mirror” can reflect an infrared laserpointer and transmit visible light so that the patient or treatingphysician or a camera will be able to see through the lens. A “coldmirror” will transmit infrared and reflect visible so that a visiblelaser pointer can be reflected while infrared can be transmitted; coldmirrors can be used, for example, in cases where it is desired toutilize an infrared fundus camera during treatment.

In some embodiments, the coupling surfaces 950, 955 of the device 945can be attached to a holder 971 (FIG. 1H) to hold the eye in place. Theholder 971 can be attached to the radiotherapy device, but preferably itis attached at a location separate from the radiotherapy device, such asa frame that is attached to the table or platform 974 which holds theradiation device. In some embodiments, the frame 972 has multiplejoints, and in some embodiments, the frame 972 is flexible or springylike a cantilever beam. The frame 972 provides for some force againstthe eye of a patient transmitted through the coupling device 945 when itis attached to the holder 971.

In some embodiments, the coupling device 945 can include material thatis radiotranslucent, or that permits at least some radiation to pass. Insome embodiments, the radiotranslucent material of the coupling device945 can be configured to permit the passage of the therapeutic x-raybeams during treatment. For example, the coupling device 945 can engagethe eye to maintain position of the eye, and the x-ray beams can bedirected to target eye tissue with a trajectory that passes through atleast a portion of the coupling device 945. Accordingly, the treatmentplanning system can plan x-ray beam trajectories without significantconsideration of where the coupling device 945 engages or is positionedon the eye.

In some embodiments, the coupling device 945 can include material thatis radiopaque, or that reduces or limits the transmission of radiation.In some embodiments, the radiopaque material of the coupling device 945can be configured to limit transmission through the material ofradiation, such as, for example, x-ray beams. For example, the couplingdevice 945 can engage the eye to maintain position of the eye, and x-raybeams that are directed to target tissue of the eye will not bepermitted to pass through, or transmission of the x-ray beams throughthe material will be substantially limited, the coupling device 945. Inthese embodiments, the coupling device 945 can be used as a shield forcritical structures of the eye (e.g., the lens, the optic nerve, thecornea, as so forth) by limiting radiation exposure to these structures.

The treatment planning system can be configured to identify or recognizethe radiopaque material and limit application of x-ray beams havingtrajectories toward the target tissue that may cross the coupling device945. For example, when the coupling device 945 engages the eye, a zoneis created outside the eye where application of x-ray beams to thetarget tissue will pass through the coupling device 945. When thecoupling device 945 is substantially round, this zone in space willproject from the target tissue through the coupling device 945 in theform of a cone, in which if the source of the x-ray beam is placed, thetrajectory of the x-ray beam will pass through the coupling device 945to the target tissue.

An axis extending from the target tissue and passing through thecoupling device 945 will represent a beam trajectory that will berequired to pass through the coupling device 945 to treat the targettissue. If the coupling device 945 includes radiopaque material, thetrajectory that passes through the coupling device 945 may not be anoptimal approach, as the material may hinder or otherwise affect thex-ray beams. Accordingly, in some embodiments, the source is relocatedoutside the space that corresponds to trajectories that pass through thecoupling device 945 to treat the target tissues, and a new trajectorycan be established that does not pass through the coupling device 945.This new trajectory will be transverse, or not parallel to, the axisthat passes through the coupling device. In some embodiments, the newtrajectory can be parallel to the axis that passes through the couplingdevice, but not collinear with the axis and not directed to the sametarget site as that of the axis. Similar new trajectories can then bereplicated with similar relationships to the axis.

In some embodiments, the coupling device 945 can include both materialthat is radiopaque and material that is radiotranslucent. In someembodiments, the radiopaque material of the coupling device 945 can beconfigured to limit transmission through the material of radiation, suchas, for example, x-ray beams, and the radiotranslucent material can beconfigured to permit transmission of radiation (e.g., x-ray beams) topass through the material. The coupling device 945 can further beconfigured to provide alignment trajectories along which the x-ray beamswill pass to the target tissue. In some embodiments, the coupling device945 can further operate as a tertiary collimator by limiting the beamsize or shape. For example, the radiotranslucent material of thecoupling device 945 can be sized and shaped as the aperture through thesecondary collimator. In such embodiments, when the x-ray beam isemitted through the radiotranslucent material, any penumbra at thecoupling device 945 can be blocked by the surrounding radiopaquematerial. In some embodiments, apertures in the radiopaque material maybe provided instead of radiotranslucent materials. Accordingly, thecoupling device 945 can further provide shielding or targetingfunctions.

Some embodiments provide that the coupling device 945 have a pluralityof apertures or portions of radiotranslucent material positionedradially around a center of the coupling device 945. The apertures canbe shaped as circles, squares, rectangles, ovals, curvilinear,irregular, annular, concentric rings, and so forth. In some embodiments,the coupling device 945 is configured to include an aperture or portionof radiotranslucent material only in a center portion of the device topermit transmission of radiation therethrough to target tissue.

In some embodiments, the coupling device 945 can have a radiopaquematerial that comprises substantially a central portion of the couplingdevice 945 (e.g., a portion of the ocular surface 960), and a portion ofthe coupling device 945 extending around a periphery, or the edges, ofthe central portion comprises radiotranslucent material. Accordingly,the central portion can operate as a shield to structures of the eye,and the x-ray beams can pass through the radiotranslucent materialduring radiotherapy. Thus, the coupling device 945 can have a largerocular surface 960 to engage the eye while still permitting x-ray beamsto reach the target tissues substantially unimpeded by the radiopaquematerial.

FIGS. 1I and 1J depict a mechanism by which the coupling device 975 canbe used to align the radiotherapy system 990. Laser pointer beam 977(which is collinear with the radiation beam in some embodiments) isemitted from radiotherapy device 990 through a collimator opening 979and reflects off a mirror 976 of the coupling device 975. In thenon-alignment case depicted in FIG. 1I, the laser pointer beam 977 willnot bounce back collinearly with the collimator opening 979, but will beoff-axis, as shown by reflection point 980. The orientation of theradiotherapy system 990 can be manually or automatically adjusted bydirect visualization of the location of the reflection point 980 or bysensors that detect the location of the reflection point 980 and adjustthe radiotherapy system 990 to bring the laser pointer beam 977 intoalignment. In the case where the laser pointer is in fact aligned (FIG.1J), the laser pointer 977 is reflected, and the reflection point 980 issubstantially collinear with the collimator opening 979.

FIG. 1K depicts the radiotherapy system with coupling device 975 inplace. A treatment axis 214, which provides a reference about whichapplication of the radiation beams are applied, is now coupled to oraligned with an system axis 211 of the radiotherapy system, about whichthe x-ray source 110 can be rotated, as indicated by arrow 112. Thex-ray source 110 can rotate about the system axis 211 with orindependent from the imaging subsystem 400 and its corresponding axis405 (also illustrated in FIG. 1D). With the treatment axis 214 alignedwith the system axis 211, and with the coupling device 975 engaging theeye 210, trajectories of the radiation beams can be determined to directthe radiation beams to be coincident with the target tissue of the eye210 of the patient 220. The defined space of the treatment axis 214, thesystem axis 211, the location of the coupling device 975, and thelocation of the x-ray source 110 provides a confined coordinate framethat can be used, for example, for directing orientation andadministration of the radiation beams.

In some embodiments, the x-ray source 110 can travel around a floatingfocal point, such as one that is defined by the treatment planningsystem and virtual model of the eye. A floating focal point is a focalpoint that can be programmed or located anywhere in the eye and moved todifferent locations during treatment, as opposed to a fixed focal point,such as the macula. In some embodiments, the x-ray source 110 can movewith six degrees of freedom around a fixed or moving axis. In someembodiments, the x-ray source 110 remains fixed in one spot to treat aneye structure in the anterior portion of the eye, or even the posteriorportion of the eye, depending on how large an area is to be treated andthe dose required.

In some embodiments, the x-ray source 110 focuses x-rays on a target bymoving to different positions around the eye 210 and delivering x-raysthrough the sclera at substantially different entry points on thesclera, but each x-ray beam reaching a substantially similar targetwithin the eye. In some embodiments, the x-ray source 110 remains in onelocation, delivering x-ray energy to and through the sclera and toregions of the eye, such as the retina, and specifically the macula. Insome embodiments, the x-ray source 110 is moved with six degrees offreedom, five degrees of freedom, four degrees of freedom, three degreesof freedom, or two degrees of freedom. In some embodiments, the x-raysource 110 is stationary and the collimator is moved or the eye or thepatient is moved to project the beam to different regions of the eye. Insome embodiments, the retina is treated by maintaining the x-ray beam inone position with respect to the sclera. The x-ray source 110 can bemoved automatically by a robotic arm or manually by the operator of thesystem. The ultimate three-dimensional position of the x-ray source 110can be dictated by the treatment plan which communicates between a modelof the eye and with the robotic arm to determine the position of thex-ray beam relative to the eye.

In some embodiments, only a small amount of movement is required of thex-ray source 110 to treat a disease of the retina, such as maculardegeneration and/or diabetic macular edema. In these embodiments, sixdegrees of freedom can be applied to the x-ray source 110, but the rangeof each degree of freedom is preferably limited so that the movementsystem only travels within a space of about 1000 cm³, 500 cm³, 100 cm³,or about 50 cm³. The speed of the robot within these volumes can bedefined such that the robot moves 0.5 cm/s, 1 cm/s, 3 cm/s, 5 cm/s.Because each fractional treatment dose is relatively short and appliedover a small distance, the robot can sacrifice speed and travel distancefor smaller size.

In some embodiments, multiple x-ray sources are used, each positioned atdifferent points in space so as to deliver a plurality of x-ray beamswhich will all converge on the target tissue, which can be one point onor in the eye. For example, the radiation system can have 3, 4, 5, or 6x-ray sources that each have different, aligned trajectories that areall configured to intersect at a treatment location within the eye,which can include, for example, the fovea 240, depicted in FIG. 1C.Application of the x-ray beams can be performed simultaneously or inseries. Treatment with a plurality of x-ray sources operatingsimultaneously can reduce treatment time, and consequently, reduce thelikelihood of patient movement during the treatment period.

In some embodiments, it is a goal of the treatment system to deliverradiation therapy substantially through the pars plana region of the eye(see FIG. 1C). Pars plana 215 is the region of the eye between the parsplicata 218 and a peripheral portion of the retina 280, the ora serrata.The pars plana 215 region of the eye contains the fewest criticalstructures enroute from the sclera 260 to the retina 280. It is throughthis the region that surgeons can inject pharmaceuticals into the eye orto perform vitrectomies because the risk of damage to ocular structuresis reduced with this approach. Likewise, radiotherapy can be deliveredto the posterior region of the eye through the pars plana region 215 tominimize the potential for damage to structures, such as the lens, andyet still reach posterior regions, such as the fovea 240, with minimalradiation reaching the optic nerve 275. The image-guided orthovoltagetherapy described herein allows such specific treatment.

In some embodiments, when a patient has an artificial intra-ocular lens,which may be unaffected by exposure to x-ray radiation, the radiotherapycan be delivered through the cornea and lens to the retina, directlythrough the central axis, the visual axis of the eye, or through thecornea. In some embodiments, treatment by x-ray radiation may beprovided at the same time as a procedure for implanting an artificialintra-ocular lens.

With continued reference to FIG. 1C, the central axis 300 of the eye istypically defined by the geometric axis 300 and begins at the center ofthe curvature of the cornea 255; this axis 300 can also be called theoptical axis or the treatment axis. The treatment axis can include anyaxis that is coincident with the treatment target. The visual axis 306is represented by a line from the center of the fovea 305 through thecenter of the pupil 217. Angle kappa (k) 213 represents the anglebetween the visual axis 306 and optical axis 300. The geometric axis 300can be defined by a perpendicular straight line or axis extending fromthe center of the cornea straight back to the retina 280. In thisdescription, this axis can also be referred to as the treatment axis.The limbus 308 is generally the transition area where the cornea meetsthe sclera or visually, the point where the pigmented region of the eyemeets the white region of the eye. The pars plana angle α 212 can bemeasured from the geometric central axis 300 and can range from about 10degrees to about 50 degrees off the central geometric axis 300. The parsplana 215 region of the eye can be related to the central axis 300 ofthe eye through angle α 212. In some embodiments, x-rays with a tightcollimation (e.g., smaller than about 6-8 mm in diameter) and a smallpenumbra (e.g., less than about ten percent at the sclera) enter thepars plana region 215 of the eye along a trajectory 250, avoiding someof the critical structures of the eye, to reach structures which are tobe treated, such as the retina 280. In some embodiments as describedherein, during the treatment, the eye can be stabilized with theassistance of physical or mechanical restraint or by patient fixation ona point so that the x-rays enter the eye substantially only in the parsplana region 215.

In certain embodiments, the patient is stabilized with respect to theaxis of the eye. If the patient or device moves, then the imagingsubsystem 400, or camera, detects the movement and turns the device offor closes a shutter over the region where the x-rays leave the device orthe collimator. In some embodiments, the x-ray source 110 is moved aboutthe eye to one or more positions determined by a treatment planningsystem, delivering radiation through the pars plana region 215 of theeye to reach the retina 280. The defined treatment axis and thetrajectory through the tissue of the eye dictate the angle of deliveryof the x-ray beam by the system relative to the treatment axis. Thetotal dose is divided across different regions of the sclera butpenetrates through the pars plana 215 region to reach the desired regionof the retina (for example, the macula or the fovea).

As shown in FIGS. 1I-1J and as explained above, the mirror 976 canreflect the laser pointer beam 977 back toward the radiotherapy system990. The reflected laser pointer beam 977 can activate a sensor 992which can provide feedback relating to the position of the laser pointerbeam 977 and inhibits or disinhibits the radiotherapy system 990.Alignment or misalignment of the radiotherapy system 990, as detected bythe sensor 992, can be the trigger for the inhibition or disinhibitionfor the radiotherapy system 990. For example, in some embodiments, thelaser pointer beam 977 can be configured such that the laser pointerlight is reflected onto the sensor 992 when the eye is within anacceptable operational orientation. Accordingly, when the laser pointerlight is reflected onto the sensor 992, the sensor 992 detects thereflected light and provides indication of the incident light to theradiotherapy system 990 or a processing module of the sensor 992 orsystem 990. The radiotherapy system 990 or processing module can beprogrammed such proper orientation of the eye and the system 990 isidentified when the sensor 992 indicates that it has received reflectedlaser pointer light. The system can then be free to emit the radiationbeams, and the radiation source can be powered to emit radiation beamsor shutters on the system can be opened to permit radiation beams to beemitted to the eye.

If, during a treatment procedure, the eye moves, and the reflected laserpointer light no longer is incident upon the sensor 992, the system isnotified by the sensor 992, indicating that the eye has moved and thatthe eye is no longer within the acceptable operational orientation.Power to the radiation emitter can then be terminated, or shutters on acollimator can be drawn, to stop emission of radiation to the eye.

In some embodiments, the reflected light or laser pointer 977 canindicate the degree of alignment between the coupling device 975 andmirror 976 and the radiotherapy device 990 from which the light source977 originates. FIGS. 1I and 1J illustrates substantial coaxialalignment of the radiotherapy device 990 with the scleral lens 950 (FIG.1I) and the geometric or visual axis of the eye 952 (FIG. 1J). In thisinstance, the reflected beam 977 and the incident beam 978 areindistinguishable as the reflected beam reflects 980 back onto thecollimator 979 where the laser pointer originates. FIG. 1I depicts thecase of misalignment where the incident beam 978 and its reflection 977reflect back do not meet on the collimator 980, 979. A camera monitoringthe status of alignment can signal the system to turn off when theincident beam 978 and its reflection 977 are not coaligned.

The head restraint 160 portion of the radiotherapy system 10 may be usedfor restraining the head of the patient 220 so as to substantiallystabilize the location of the patient's eye 210 relative to theradiotherapy treatment system 10. The physician applying the treatmentcan align the central axis 300 of the patient's eye with the x-raysource 110. The restraint 160 can be configured to maintain thepatient's position during the treatment. If the patient moves away fromthe restraint 160 or moves their eyes from the restraint, then the x-raysystem can be turned off (e.g., by gating) manually or automatically andthe patient's position readjusted.

In general terms, the patient's head is maintained in position with thehead restraint 160 while the eye 210 is tracked by the imaging system400 and/or treatment planning system and the x-ray source 110 is movedso that the x-ray beam enters the eye through the pars plana region 215;the x-rays, therefore, penetrate to the target regions of the retina andreduce the likelihood of significant damage as they pass through eyetissue toward the retina.

The treatment planning system 800 (FIGS. 1B and 2E) provides thephysician interface with the system 10. The treatment plan is developedbased on pre-treatment planning using a combination of biometricmodalities including an imaging subsystem 400 that can include, forexample, fundus photography, or optical coherence tomography, CT scans,MRI scans, and/or ultrasound modalities. The information from thesemodalities are integrated into a computer-generated virtual model of theeye which includes the patient's individual anatomic parameters(biometry) as well as the individual's specific disease burden. Any orall of these modalities can be utilized by the system in real time orintegrated into the system prior to treatment. The treatment plan isoutput, for example, on the interface display 130 module of theradiotherapy system 10. The physician can then use the virtual model inthe treatment plan to direct the radiation therapy to the disease usingthe radiotherapy system 10.

As used herein, “eye model” or “model of the eye” refers to anyrepresentation of an eye based on data, such as, without limitation, ananteroposterior dimension, a lateral dimension, a translimbal distance,the limbal-limbal distance, the distance from the cornea to the lens,the distance from the cornea to the retina, a viscosity of certain eyestructures, a thickness of a sclera, a thickness of a cornea, athickness of a lens, the position of the optic nerve relative to thetreatment axis, the visual axis, the macula, the fovea, a neovascularmembrane, a curvature of a cornea or a retina, a curvature of a scleralregion, and/or an optic nerve dimension. Such data can be acquiredthrough, for example, imaging techniques, such as ultrasound, scanninglaser ophthalmoscopy, optical coherence tomography, other opticalimaging, imaging with a phosphor, imaging in combination with a laserpointer for scale, CT scan with or without contrast, and/or T2, T1, orfunctional magnetic resonance imaging with or without contrast. Suchdata can also be acquired through keratometry, refractive measurements,retinal nerve-fiber layer measurements, corneal topography, directcaliper measurement, etc. The data used to produce an eye model may beprocessed and/or displayed using a computer. As used herein, the term“modeling” includes, without limitation, creating a model.

The eye model is a virtual model which couples the anatomy of the eyewith the coordinate system of the radiotherapy device. The eye model canbe based on the geometry of the ocular structures and can be derivedwith parametric data and mathematical formulas to generate the model.Alternatively, the ocular geometries are derived from cross-sectionalimaging, such as from CT scans or MRIs. With the treatment axis definedand the ocular anatomy defined, the coupling device can contact theocular surface and link to the radiotherapy device via the eye model.The radiotherapy device is then positioned based upon the eye model.

In some embodiments, real time visualization of the eye can be utilizedby emitting a laser that is aligned with the trajectory of the radiationbeam. Observation of the location of the laser can be used to visuallyindicate proper orientation of the radiation beam trajectory. Forexample, it may be desired that the edge of the radiation beam be placedabout 1 mm to about 4 mm from the limbus so as to avoid criticalstructures. As the laser pointer from the radiotherapy device reaches aspot 1-4 mm from the limbus, the radiotherapy eye model then uses theaxial parameters of the eye to direct the radiotherapy device to thecorrect angle relative to the structure within the eye.

In some embodiments, the laser pointer is oriented on the sclera at apoint that is desired to pass through the sclera. Once the laser pointerlocates the desired location, the laser pointer is fixed on that portionof the sclera while the radiation source is oriented with respect to thedesired location on the sclera, such that when the radiation source isactivated and a radiation beam is emitted therefrom, the radiation beamwill pass substantially through the desired location and a targetlocation within the eye. A portion of the eye through which theradiation beam passes can be referred to herein as a traversal zone(e.g., 515 on FIG. 2D), or intersecting zone.

With continued reference to FIG. 1B, which shows a schematic overview ofthe treatment planning system 800, depicted by the background ovalshape, and illustrating a global interconnect between four subsystems.The treatment planning system 800 directs the four subsystems towardtreatment of the region and/or disease indicated by the physician. Thefour subsystems in general terms include an x-ray subsystem 700, acoupling subsystem 500, an electromotive subsystem 600, and an imagingsubsystem 400. These subsystems or modules interact to provide anintegrated treatment to the eye of a patient.

The subsystems work together to coordinate the treatment planning system800. The treatment planning system (TPS) 800 also provides the interfacebetween the physical world of the eye, the physical components of thesystem, and a virtual computer environment which interacts with thephysician and treatment team and contains the specific patient anddisease information. The coupling system 500, primarily, and the imagingsystem 400, secondarily, help link the physical world and the virtualworld.

Within the virtual world, the treatment planning system creates acomputer-generated virtual model of the patient's eye 505 based onphysical and biometric measurements taken by a health practitioner orthe imaging system 400 itself. The computer model 505 (FIG. 2D) in thevirtual world further has the ability to simulate the projection 510 ofan x-ray beam 520 from a radiation system 524 through an anterior regionof the eye, which can include a traversal or intersecting zone 515, tothe structure 514 to be treated based on different angles of entry intothe eye. The model can also identify and include important eyestructures, such as the optic nerve 512, to consider during thetreatment planning process. The virtual world also contains thephysician interface to control the device 524 and interface the devicewith respect to the physical world, or that of the actual physicallytargeted structure. After integrating the inputs from the physician andmodeling the beam angles and desired direction to direct the therapy,the virtual world outputs the information to the electromotive subsystemto move the x-ray device to the appropriate position inthree-dimensional space. The coupling subsystem 500 (in the physicalworld) can include a mechanism to determine the angle of incidence ofthe x-ray beam with respect to the surface of the eye using one or morelaser or angle detectors, as discussed above.

In some embodiments, the coupling system 500 contains a camera 518 whichcan image a spot (real, reflected, fiducial, or projected fiducial) 516on or in an eye; the camera can also visualize structures such as thepupil, cornea, sclera, limbus, iris, fundus, optic nerve, macula, or alesion to be treated. Information from the camera is then preferablytransferred to the virtual eye model 522 and again to the motion andradiotherapy system 524. In certain embodiments, the coupling system 500is a physical connection with the eye. In some embodiments, the couplingsystem 500 is not a physical link but is a communication link between alens on the eye and a detection system. For example, a lens can be acommunication beacon to relay eye position to the system 500. In someembodiments, the lens can contain markers that are imaged by the imagingcamera 518, through which the next stage in the therapy can bedetermined. In some embodiments, a combination of these techniques isused.

In some embodiments, the position of the eye and the x-ray source areknown at all times, and the angles of entry of the x-ray can thereforebe realized. For example, the central axis of the eye can be determinedand defined as the treatment axis; the x-ray source offset a known anglefrom the central axis. The central axis, or treatment axis, in someembodiments can be assumed to be the axis which is perpendicular to thecenter of the cornea or limbus and extends directly posterior to theretina, as discussed previously. In some embodiments, the couplingsubsystem can detect the “glint” or reflection from the cornea. Therelationship between the glint and the center of the pupil is constantif the patient or the patient's eye is not moving. If the patient moves,then the glint relative to the center of the pupil is not in the sameplace. A detector can detect when this occurs, and a signal can be sentfrom the virtual world to the x-ray device to turn the x-ray device offor to shutter the system off. Alternatively, the coupling system cancompare the center of a scleral lens relative to the center of thecornea. Both the lens and the cornea have respective glints and theiralignment ensures that their centers are perpendicular to one another.

The information obtained from the coupling subsystem is preferably sentto the computer system and to the virtual eye model. The imagingsubsystem 400 captures an image of the eye in real time with a camera1460, depicted in FIG. 2C, and feeds the data into the software programthat creates a virtual model of the eye. In combination with thephysical world coupling system 500, the predicted path of the x-ray beamthrough the eye can be created on the virtual image. Depending on theregion to be treated, the electromotive system and/or x-ray system canbe readjusted; for example, a robot arm can move the x-ray source 110 toa position to send a radiation or x-ray beam to a location on or in theeye based on the model of the eye as created by the TPS and as capturedby the imaging system 400.

In certain embodiments, the radiotherapy generation system 100 caninclude an orthovoltage (or low energy) radiotherapy generator as thex-ray subsystem 700, as discussed in further detail with reference toFIG. 1A, a schematic of the device. The radiotherapy generationsubsystem 110 generates radiotherapy beams that are directed toward theeye 210 of the patient 220 in FIG. 1A. In certain embodiments, theradiotherapy control module 120 includes an emitter 200 that emits adirected, narrow radiotherapy beam generated by the radiotherapygeneration subsystem 110.

As used herein, the term “emitter” is intended to have its plain andordinary meaning, and the emitter can include various structures, whichcan include, without limitation, a collimator and/or a filter. In someembodiments, the control module 120 is configured to collimate the x-raybeams as they are emitted from the radiotherapy generation subsystem110.

The x-ray subsystem 700 can direct and/or filter radiotherapy raysemitted by the x-ray tube so that only those x-rays above a specificenergy pass through the filter. In certain embodiments, the x-raysubsystem 700 can include a collimator through which the pattern orshape of an x-ray beam is determined. The filtering of the sourcepreferably determines the amount of low energy inside the x-ray beams aswell as the surface-depth dose as described in ensuing figures. In someembodiments, it is desirable to deliver orthovoltage x-rays with asurface-to-depth dose less than about 4:1 to limit dose accumulation atthe surface of the eye. In some embodiments, it is desirable to have asurface-to-depth dose less than about 3:1 or about 1.5:1 but greaterthan about 1:1 when using orthovoltage x-rays. The surface-depth dosecan also be altered by changing the maximum beam energy leaving thex-ray tube. For example, for a disease on the surface of the eye such aspterygia or to treat post-trabeculoplasty scarring, the maximum beamenergy leaving the x-ray tube may be lower, such as about 40 keV, about50 keV, or about 60 keV. In these diseases it may be desirable to haveabout a 30:1, 50:1, or 100:1 surface to depth ratio. Therefore, theradiotherapy control system can control one or more of the power outputof the x-ray, the spectrum of the x-ray, the size of the beam of thex-ray, and the penumbra of the x-ray beam.

In certain embodiments, the electromotive subsystem 600 of theradiotherapy system may move the x-ray source and the collimator todirect a narrow radiotherapy beam emitted from the x-ray source toirradiate specific regions of the patient's eye 210 by directing energyonto or into targeted portions of the eye 210, while at the same timeavoiding irradiation of other portions of the eye 210. For example, thesystem 10 may target a structure of the posterior region of the eye,such as the retina, or a structure on the anterior region of the eye,such as the trabecular meshwork, the sclera, the cornea, the ciliaryprocesses, the lens, the lens capsule, or the canal of schlemm. Thesystem 10 can deliver radiotherapy to any region of the eye, including,but not limited to, the retina, the sclera, the macula, the optic nerve,the ciliary bodies, the lens, the cornea, Schlemm's canal, the choroids,the capsular bag of the lens, and the conjunctiva.

In certain embodiments, the x-ray subsystem 700 can collimate the x-rayto produce a narrow beam of specified diameter and shape. For example,in certain embodiments using a collimator, the diameter of thecollimator outlet may be increased or decreased to adjust the diameterof the radiotherapy beam emitted by the collimator. In certainembodiments, the x-ray subsystem 700 can emit a beam with a diameter ofabout 0.1 mm to about 6 mm. In certain embodiments, the x-ray subsystem700 can emit a beam with a diameter of less than about 0.1 mm. Incertain embodiments, the x-ray subsystem 700 can emit a beam with adiameter of between about 0.5 mm and about 5 mm. As described in furtherdetail below, narrow beams and virtual models are useful to ensure thatthe energy is applied to a specific area of the eye and not to otherareas of the eye.

In some embodiments (FIG. 2B′-2B″), the radiation control module canemit an x-ray beam with a circular 1212 or non-circular 1214 shape; insome embodiments, the radiation control module can emit an x-ray beamwith a rectangular shape 1214 or a square shape. In some embodiments,the radiation control module can emit an x-ray beam with an arc shape oran elliptical shape or a doughnut configuration 1217 through a circularcollimator 1215 with an opaque region 1218 in the center. In someembodiments, the collimator 1215 can include a conical-shaped opening1232, such as depicted in FIG. 2B″″, for providing a precisely shapedbeam 1200. In some embodiments, the collimator 1215 has multipleopenings (see, e.g., FIG. 2B″″) such that the x-ray has a specular,dotted configuration when it reaches the sclera and retina. The speckledconfiguration of the x-ray, which can be termed “micro-fractionation”,may allow for an improved safety profile because less radiation will beapplied to the retina and choroid normal blood vessels.

In certain embodiments, the radiotherapy system 10 allows for selectiveirradiation of certain regions of the eye without subjecting other areasof the eye to radiation by using a narrow, directed treatment beam, thetreatment beam dictated by the specific anatomy of the patient's eye.For example, the radiotherapy control module 120 can direct radiotherapybeams generated by the radiotherapy generation module 110 to a patient'smacula, while substantially avoiding radiation exposure to otherportions of the patient's eye, such as the lens, the trabecularapparatus, and the optic nerve.

By selectively targeting specific regions of the eye with radiationbased on knowledge of the anatomy of the eye and linking the radiationsystem to the anatomy for treatment purposes, areas outside of thetreatment region may avoid potentially toxic exposure to radiation. Insome embodiments, the x-ray beam follows a trajectory 250 that entersthe eye through the pars plana region 215 which is a zone of the sclera260 between the iris 270 and the retina 260. By directing the beam tothis region and limiting the penumbra or scatter of the beam usingspecialized collimators, the beam can be localized onto an eye structurewith minimal photon delivery to other structures of the eye, such as thecornea 255, the ciliary body and fibers 216 and other structures.

In certain embodiments, the radiotherapy treatment system 10 can includea shutter for controlling the emission of radiotherapy beams. Theshutter may comprise a material opaque to the radiation generated by theradiation generation module 110. In certain embodiments, a shutter maybe used to control the emission of beams from the radiotherapygeneration module 110. In certain embodiments, a shutter may be used tocontrol the emission of beams from the radiotherapy control module 120.In certain embodiments, the shutter may be internal to either of saidmodules 110 and 120, while in certain embodiments, the shutter may beexternal to either of said modules 110 and 120. In some embodiments, thesystem 10 is turned off to stop x-ray delivery, and in certainembodiments, the x-ray source 110 is turned off or its intensity turneddown to limit or stop x-ray delivery to the target. In certainembodiments, the shutter or aperture changes shape or size.

In certain embodiments, and as explained above with respect to FIG. 1A,the radiotherapy treatment system 10 can deliver radiotherapy beams fromone angle. In certain embodiments, the radiotherapy treatment system 10can deliver radiotherapy beams from more than one angle to focus thebeams on the treatment target. Certain embodiments of the system 10 thatcan deliver radiotherapy beams from more than one angle can include aplurality of stationary radiotherapy directing modules. The stationaryradiotherapy modules can be positioned in a wide variety of locations todeliver radiotherapy beams to the eye at an appropriate angle. Forexample, certain embodiments of the radiotherapy treatment system 10include five radiation source module-radiation directing module pairsthat are connected to the radiotherapy treatment system 10 in such a waythat they are spaced equidistantly around a circumference of animaginary circle. In these embodiments, the power supply could be aswitching power supply which alternates between the various x-raygenerators. Certain embodiments of the system 10 that can deliverradiotherapy beams from more than one angle can also include moving theradiotherapy directing module. Certain embodiments of the system 10 thatcan deliver radiotherapy beams from more than one angle can also includemoving the radiotherapy source using an electromotive subsystem 700(FIG. 1B), such as a robot.

In some embodiments of the present disclosure, orthovoltage x-rays aregenerated from the x-ray generation module 700. X-ray photons in thisorthovoltage regime are generally low energy photons such that littleshielding or other protective mechanisms can be utilized for the system10. For example, diagnostic x-rays machines emit photons withorthovoltage energies and require minimal shielding; typically, only alead screen is used. Importantly, special rooms or “vaults” are notrequired when energies in the orthovoltage regime are used. Diagnosticx-ray machines are also portable, being transferable to different roomsor places in the clinical environment. In contrast, linear acceleratorsor LINACS which typically deliver x-rays with energies in the MeV rangerequire thickened walls around the device because higher energy x-rayphotons have high penetration ability. Concomitant with the higherenergy photons, LINACS require much greater power and machinery togenerate these high energy photons including high voltage powersupplies, heat transfer methodologies, and internal shielding andprotection mechanisms. This increased complexity not only leads tohigher cost per high energy photon generated but leads to a much heavierdevice which is correspondingly more difficult to move. Notably, asdescribed above and demonstrated experimentally, as discussed below, MeVphotons are not necessary to treat superficial structures within thebody and, in fact, have many disadvantages for superficial structures,such as penetration through the bone into the brain when onlysuperficial radiation is required.

X-ray Subsystem

The x-ray subsystem 700 generates x-rays and can include a power supply,a collimator, and an x-ray tube. In certain preferred embodiments, thex-ray subsystem 700 includes an orthovoltage x-ray generation system1070 to produce orthovoltage x-rays with energies between 10 keV and 500keV or even up to 800 keV. This type of x-ray generation scheme includesa high voltage power supply that accelerates electrons against atungsten or other heavy metal target, the resulting collision thengenerating electromagnetic energy with x-ray energies.

Orthovoltage or low energy x-ray generators typically emit x-rays in therange from about 1 keV to about 500 keV or even up to about 1 MeV. Insome embodiments, the system described herein emits x-rays with photonenergies in the range from about 25 keV to about 100 keV. The use of lowenergy x-ray systems allow for placement of these x-ray treatmentsystems in outpatient centers or other centers and will not require theoverhead and capital requirements that high energy (MeV or gamma) x-raysystems require. In the treatment of ophthalmologic disorders, such asAMD, placement in the ophthalmologist office or close to theophthalmologic office is important because the ophthalmologists cantreat many more patients, a very important component when treating adisease that afflicts millions of patients. If the device were limitedto operating within vaults inside radiation oncology centers, the numberof treatable patients would be much more limited because of access,cost, competition with other diseases, and other logistics.

The radiation generation module in some embodiments is composed ofcomponents that are arranged to generate x-rays. For example, a powersupply generates current which is adapted to generate and accelerateelectrons toward an anode, typically manufactured from a heavy metalsuch as tungsten, molybdenum, iron, copper, nickel, or lead. When theelectrons hit one of these metals, x-rays are generated.

An exemplary set of x-ray spectra is shown in FIG. 1F. The term “kVp”refers to the maximum (peak) voltage of the x-ray power supply. It istypically identical to the maximum photon energy delivered by the x-raysource (keV). When x-rays are generated by high voltage electricity, aspectrum of x-ray at various x-ray levels is obtained, a typicalspectrum set shown in FIG. 1F. The maximum voltage is typicallyidentical to maximum x-ray photon energy. For example, the 80 kVpspectra in FIG. 1F has a maximum of 80 keV with a leftward tail of lowerenergy radiation. Similarly, the 60 kVp spectrum has a maximum of 60 keVwith a similar leftward tail. All spectra in the figure have beenfiltered through 3 mm of Aluminum. Filtering shapes the spectral curve.Lower wavelengths are filtered to a greater degree than the higherwavelengths. Filtering of the raw spectra is important to customize thex-ray energy for the application at hand where the superficial energy,if not filtered, would be absorbed by the superficial structures of theeye (e.g., sclera). To the extent that it is desired that x-ray energyreach the structures of the retina with minimal energy absorption by theanterior structures of the eye, filtering of the raw spectra isimportant to the system; with filtering, the resulting spectrum containsa greater amount of high energy photons than low energy photons,essentially a low-pass filter. As described, for some disease processes,it is desirable to have a predominance of low energy x-ray reach theanterior structures of the eye in which case the lower voltages will beused with correspondingly lower keV peaks. Adjustment of the power onthe power supply will result in a decrease in the peak voltage ofx-rays, limiting the amount of higher energy photons. In someembodiments, it may be desirable that a non-uniform filter be used. Forexample, the filter may have varying thicknesses across it toaccommodate varying differences in the x-ray spectra in one treatmentregion.

A power supply 150 as shown in FIG. 1A powers the radiation module. Thepower supply 150 is rated to deliver the required x-ray with a givencurrent. For example, if 80 KeVp x-rays are being delivered from thesource at 10 mA, then the power required is 800 W (80 kilovolts×0.01 A).Connecting the power supply to the x-ray source is a high voltage cablewhich protects and shields the environment from the high voltage. Thecable is flexible and in some embodiments has the ability to be mobilewith respect to the power supply. In some embodiments, the power supplyis cooled with an oil or water jacket and/or convective cooling throughfins or a fan. The cooling fluid can move through the device and becooled via reservoir outside the system 10.

Electromotive Subsystem

FIGS. 2A and 12A depict embodiments of the electromotive subsystem 600of the treatment system 1000 illustrated in FIG. 1B. The subsystem is anadvantageous component of the therapeutic system because it controls thedirection and the size of the x-ray beam in relation to the anatomy ofthe eye and the disease to be treated. In general terms, theelectromotive subsystem is directed in the space of the globalcoordinate system 1150 by the personalized eye model created from thepatient's biometric data. The data from the model is transferred throughthe treatment planning system to the electromotive subsystem 600 todirect the x-ray beam to the target on or in the eye.

In certain embodiments, the system can include a collimation system3315, a shutter system, and an electromechanical actuation system tomove the x-ray source and/or collimators. Referring to FIGS. 2A and 12A,orthovoltage x-ray source, or tube, 1070, 3325 is depicted. Collimators1030, 1040, 1052, 3315 are calibrated to produce a small collimated beam1062 of x-ray photons; in a preferred ophthalmic embodiment, the tightlycollimated beam 1062 has an area of from about 1 mm² to about 20 mm² ina circular or other shape and a diameter of from about 0.5 mm to about6.0 mm. Multiple collimators allow for improved penumbra percentages;the smaller the penumbra, the finer the application of x-rays to aspecified structure. FIGS. 2B′-2B′″ depict embodiments of collimatordesigns in which a variety of collimator configurations are depicted.For example, FIG. 2B′″ depicts a collimator configuration in which adoughnut, or annular, shape of x-rays is generated; FIG. 2B″″ depicts acollimator configured with a nozzle, or conical, shape 1232 to limit thepenumbra or create a substantially uniform radiation beam. Othercross-sectional shapes can include, for example, concentric rings, anellipse, a circle, a polygon, and a crescent. The collimators, operatingin conjunction with filters 1010, 1020 preferably cause the x-rays toleave the collimator in a beam 1062 having a substantially parallelconfiguration.

In certain embodiments, electromotive system 3300 is customized to treatthe eye with doses of radiation in a range of positions 3335. The rangeof positions 3335 is limited because the eye and treatment volume aresmall, and the source is positioned relatively close to the treatmentregion. As determined by the other components of the system as well asthe ocular geometry, x-ray tube 3325 may only move within a volume ofabout 1 cm³ to about 5 cm³ for the entire treatment program. Alsodictated by the x-ray tube size and energy, the time for movementthrough this volume may take place over a period of minutes which limitsthe size of the motors required to run the electromotive system andallowing for a table top positioning system 3300. The limited movementof the positioning system also allows the cooling tubes 3345 and powersupply tubes 3322, leading from the power supply 3320, to be relativelyconstrained and not move with the tube, further simplifying the system.Because the system is customized for treating the eye, many elements ofthe x-ray generation system are smaller than, for example, linearaccelerators. Customization for the eye allows more flexibility of thesystem as far as placement in a greater number of locations andphysician usability.

The electromotive subsystem, or control system, 600 interacts with andis under the direction of the global treatment planning system 800 inFIG. 1B. The electromotive subsystem 600 receives commands from thetreatment planning system 800 which can dictate among other things, thelength of time the x-ray machine is turned on, the direction of thex-ray beam with respect to the eye target using data from the eye modelor treatment planning system, the collimator size, and the treatmentdose. The eye target 1300 and the control system 600 can be linked inglobal coordinate space 1150 which is the basis of the coupling system.The treatment planning system 800 directs the therapy using globalcoordinate system 1150. The x-ray control system 600 dictates thedirection and position of the x-ray beam with respect to the oculartarget and moves the x-ray source into the desired position as a resultof commands from the treatment planning system 800.

In some embodiments, the collimators and/or the x-ray source can beplaced on a moving wheel or shaft (1100, 1110, 1120) with one or moremanual or automated degrees of freedom allowing the beam to be moved toa multitude of positions about the globe of the eye. In someembodiments, the x-ray source 1070 is movable with greater than onedegree of freedom such as with a robot or automated positioning system3300. The robot moves the x-ray source with respect to a globalcoordinate system such as a Cartesian coordinate system 1150 or a polarcoordinate system. The origin of the coordinate system can be anywherein physical space which is convenient. In some embodiments, the x-raysource is movable with four, five, or six degrees of freedom. In someembodiments, a robot is also utilized to move any of the othercomponents of the x-ray control system such as the collimators. In someembodiments, the collimators are controlled with their ownelectromechanical system.

The electromotive subsystem can also contain one or more shutters toturn the beam on and/or off in an instant if desired (for example, ifthe patient were to move away). The x-ray source 1070 and/or collimatorscan move in any axis in space through an electromechanical actuationsystem (1100, 1110, 1120).

The x-ray coupling subsystem 500 integrates with the x-ray generationsubsystem 700 under the umbrella of the treatment planning system 800.Also depicted in FIG. 2A, and in more detail in FIG. 2C, is at least onelaser pointer or other relatively collimated light source (e.g., a lightemitting diode with a small angle of divergence) 1060 (1410 in FIG. 2C)which can serve multiple purposes as described. In some embodiments, thelaser pointers 1060 couple with the direction of the collimated x-raybeam 1062 so that the centroid of the laser beam is approximatelyidentical to the centroid of the x-ray beam 1062 so as to have a visiblemarker as to where the x-ray beam is being delivered. Because x-rays arenot visible, the laser pointers serve to identify the direction of thex-ray beam relative to other parts of the radiotherapy system. Where thecenter of the x-ray beam is directed, the center of the laser beam iscorrespondingly directed as well as shown in FIG. 2C.

Radiotherapy Coupling Subsystem

A third major subsystem of the present disclosure is the couplingsubsystem or module 500. In general terms, the coupling module 500coordinates the direction of the x-ray beam position to the position ofthe eye. As depicted in FIGS. 2A-2D and described above, someembodiments include laser pointer 1060 (one or more may be desired) thatis collinear with the x-ray beam. In some embodiments, the laserpointer(s) allows for detection of the angles of incidence of the laserbeam 1500 (FIG. 3A) with respect to the sclera or other surface theyimpinge upon. The angles of incidence 1510, 1520 can be defined by twoorthogonal entrance angles (θ, φ) on the sclera or other surface.Centroids of the one or more laser pointers 1060 preferably coincidewith the centroid of the x-ray beam as it impinges on the sclera orother surface.

As will be described in greater detail below, the laser pointer can alsoserve an important purpose in the imaging subsystem which is to providea visual mark (FIG. 3A) 1570 on a surface of an eye 1600 when the eye isimaged by the camera 1550 and digitized or followed in the imagingsubsystem. With the visual mark 1570 on the digitized image and theangles of incidence 1510, 1520 of the laser beam 1500, computergenerated projections 1700, 1730 of the x-ray (or laser) (FIG. 3B) canbe produced on a computer-generated (virtual) retina 1720. In someembodiments, the projections 1700, 1730 are the same, and in someembodiments, the projections can be distinct. For example, in someembodiments, the projection 1700 external to the eye may have differentcharacteristics (e.g., trajectory, penumbra, etc.) than does theprojection 1730 within the eye.

The computer-generated virtual retina 1720 (FIG. 3B) is described infurther detail below and is a component of a virtual ocular model and isobtained via real data from an imaging system such as, for example, anOCT, CT Scan, MRI, A- or B-scan ultrasound, a combination of these, orother ophthalmic imaging devices such as a fundoscopy and/or scanninglaser ophthalmoscopy. In addition to the retina 1720, x-ray delivery toany structure within the eye can be depicted on the virtual ocular model1725.

As shown in FIG. 3A, laser beam 1500 is shown as the mark 1570 on screen1590, which is a depiction of the image seen by the camera 1550 and thenin digitized form within the treatment planning system 800. With anglesθ 1520 and φ 1510 and the location of the mark 1570 of the laser pointeron the digitized image of the eye 1600, the path 1730 through a “virtualeye” 1725 can be determined in a computer system 1710 (FIG. 3B). If theposition is not correct, a signal can be sent back to the electromotivemodule in order to readjust the targeting point and/or position of thelaser/x-ray.

In certain embodiments, a second camera can be used so as to detect theangles of the laser pointer and x-ray beam. These angles can be used todetect the direction of the x-ray beam and send a signal to theelectromotive system for re-positioning. This feedback system can ensureproper positioning of the electromotive subsystem as well as correctdosing of the x-ray irradiation to the eye.

In some embodiments, an analogue system is used to detect the positionof the eye. In these embodiments, the target structure, the eye, isassumed to be in a position and the x-ray control system positions thex-ray source around the globe of the eye, then applying thepre-determined amount of radiation to the eye structure.

In certain embodiments, as depicted in FIG. 1E, a physical connection tothe eye is used for direct coupling between the eye and the radiotherapysystem. In these embodiments, a connection between the eye and thesystem can be mediated by a lens, such as a scleral contact lens 935. Aphysical link between the lens 935 and the system 10 is then provided bystructure 175 which directly links to the radiotherapy system 10. Thescleral lens 935 can be a soft or hard lens. The lens 935 can furthercontain one or more connections so that suction can be applied to thesclera so as to stabilize the eye during the therapy.

The scleral lens 935 and associated attachments can be used to localizethe eye in space. When the position of the sclera is known with thelens, the position of the eye is known as well. The eye is then coupledto the radiotherapy device 10. In some embodiments, the connectionbetween the contact lens and the radiotherapy device 10 is anon-mechanical connection in that the connection is an optical one suchas with a laser pointer or one or more cameras to detect the actualposition of the eye relative to the radiotherapy system. The position ofthe eye in physical space is used to simulate the position of the beamsin the virtual eye model and then back to the physical world to placethe x-ray system to deliver the desired beam direction, angles,positions, treatment times, etc.

In some embodiments (e.g., see FIG. 2G), a schematic of the alignmentsystem is depicted for radiosurgery device 2745. The treatment axis2735, as described, is represented by a line perpendicular from thesystem, through a patient interface (e.g. a scleral lens), to theposterior pole of the eye 2720. A camera 2740 can image the region atthe front of the eye or the region where the laser pointer 2765 exits.The macular lens and guide 2730 can contain a mirror which can reflectthe laser pointer beam back on to the radiosurgery system, thereflection being detectable by the camera 2740. When the radiosurgerysystem and the mirror are perpendicular to one another, the entiresystem is then aligned along the treatment axis 2735 (as described abovewith respect to FIGS. 1I and 1J). Similarly, this type of alignmentsystem can also be used to gate the radiotherapy system to misalignmentor to patient/eye movement. For example, the reflection from the mirrorcan communicate with a sensor. In the absence of direct communicationbetween the reflected beam and the sensor, the radiotherapy system canbe gated off.

In some instances, it is desirable to know the scatter dose of the x-raybeam being delivered to a treated structure within the eye. For example,when neovascularization is being treated in the retina with a beamtraveling through the sclera, scatter to the lens or optic nerve may bemodeled. In some instances, it may be desired to know the dose to theneovascular membrane on the retina, the primary structure to be treated.

Imaging Subsystem

Another advantageous feature of embodiments described in this disclosureis the imaging subsystem 400, which can also serve as an eye trackingsystem (FIG. 4) and offers the ability to couple patient movement or eyemovement with the other subsystems above. This subsystem 400advantageously ensures that the patient's eye 2010 does not grossly moveout of the treatment field 2060. Camera 2055 can be the same camera 1550in FIG. 3A. The camera 2055 delivers an image to screen 2050. The imagedlaser spot 2052 is also shown on screen 2050. The video screen 2050 canbe the same video screen 1710 in FIG. 3B. Field 2060 in FIG. 4 is thezone within which the eye can move; if the eye 2010 moves outside thezone 2060 on the screen, then the radiation source is either turned off,shuttered off, or otherwise disengaged from the eye 2010. In someembodiments, when an image of the eye 2030 reflects that the eye 2010has moved out of field 2060, a signal 2090 is sent to the x-ray controlsystem (FIG. 2A) to turn the shutter off. Aside from ensuring that theeye remains within the treatment field, the imaging system couples tothe other subsystems by enabling projection of the laser pointer/x-raybeam 2052 on the back of the computer generated virtual eye.

In some embodiments, the imaging subsystem is composed of two or morecameras which are used to create a three-dimensional rendering of theeye in space, the three-dimensional rendering then integrated into theoverall treatment scheme.

Treatment Planning System

The treatment planning system 800 is, in part, a virtual system and isdepicted in FIG. 1B; it integrates all of the inter-related modules andprovides an interface for the health care provider as well. The planningsystem 800 is the “brains” of the system 10 and provides the interfacebetween the physician prescribing the therapy and the delivery of thetherapy to the patient. The treatment planning system integratesanatomic, biometric, and in some cases, geometric assumptions about theeye “the virtual eye model” with information about the patient, thedisease, and the system. The information is preferably incorporated intoa treatment plan, which can then direct the radiation source to applyspecific doses of radiation to specific regions of the eye, the dosesbeing input to and output from the treatment planning system 800. Incertain embodiments of the treatment planning system 800, treatment withradiation may be fractionated over a period of days, weeks, or months toallow for repair of tissues other than those that are pathologic or tobe otherwise treated. The treatment planning system 800 can allow thephysician to map the treatment and dose region and to tailor the therapyfor each patient.

Referring to FIG. 2E, the treatment planning system 800 forms the centerof a method of treatment using radiosurgery system 10. In certainembodiments, the imaging module 400 of the system 10 includes an eyeregistration and imaging system 810. In certain embodiments, theeye-tracking system is configured to track patient movement, such as eyemovement, for use by the treatment planning system 800. The eye-trackingsystem 810 can calculate a three-dimensional image of the patient's eyevia physician inputs, and can include real-time tracking of movement ofthe patient's eye. The eye-tracking system obtains data that becomes afactor for determining radiotherapy treatment planning for a number ofmedical conditions relating to the eye, as described above. For example,the eye-tracking system may create an image of the posterior region ofthe patient's eye using the data it obtains. In certain embodiments, thedata can be transferred via cable communication or other means, such aswireless means, to the processing module 140 of the radiotherapytreatment system 10. In certain embodiments, the processing module 140may process data on the patient's eye and present an image of thepatient's eye on the interface display 130. In certain embodiments, theinterface display 130 may present a real-time image of the patient'seye, including movement of the eye.

In certain embodiments, the eye-tracking system obtains data on thepatient's eye while the patient's face is placed approximately uprighton and secured by the articulated head restraint 160 such that thepatient's eyes face substantially forward, in the direction of theimaging module 400. In certain embodiments, the eye-tracking system mayinclude an alignment system, adjustable using a joystick. The joystickcan be tilted horizontally, vertically, or both horizontally andvertically, on a fixed base, in order to adjust the location and/orimage displayed on the interface display 130 by the imaging module 400.

Another feature of the present disclosure is an integrated plan fortreatment. The scale of the device as well as a limitation that thedevice treat a specific anatomy limits the scope of the treatmentplanning system which also allows for economies of scale. It ispreferable that the x-ray beams be focused so that they apply radiationselectively to target regions of the eye and not to other regions of theeye to which high x-ray doses could be toxic. However, in someembodiments, the eye is the only anatomic region that is treated. Incertain embodiments, the retina is the target for the ophthalmictreatment system; one or more beams would be directed to regions of theretina as they pass through the sclera. For treatment planning purposes,it is preferable to know the three-dimensional position of the eye andretina with respect to the output beam of the system. The treatmentplanning system incorporates detailed images and recreates the geometryof the eye and subsequently directs the x-ray system to manipulate thex-ray output so that the output beam points in the target direction. Insome embodiments, the x-ray system is directed and moved automatically.

The treatment planning system 800 may utilize, or be coupled to, imagingsystems such as, for example, optical coherence tomography systems(OCT), ultrasound imaging systems, CT scans, MRI, PET, slit lampsmicroscopy systems, direct visualization, analogue or digitalphotographs (collectively referred to as Biometry Measurements 820). Insome embodiments, these systems are integrated into real-time feedbacksystems with the radiotherapy device such that second be second systemupdates of eye position and status can take place. Although relativelysophisticated, the system 800 may be limited to the ophthalmic regionand therefore takes advantage of specific imaging equipment onlyavailable for the eye.

In some embodiments, the treatment planning system incorporates theentire soft tissue and bony structures of the head of a patient. Themodel incorporates all the anatomic structures so that obstructinganatomic regions can be excluded from the treatment. For example, thetreatment plan incorporates the nose, the forehead, and associated skinand cartilage to dictate the directionality of the radiotherapy beamwith respect to the eye. In some embodiments, these structures arerelated to the global coordinate system and aid in tracking and treatingregions of the eye.

In some embodiments, the treatment planning system incorporates physicalmodeling techniques such as Monte Carlo (MC) simulation into thetreatment plan so that the real time x-ray doses can be delivered to theocular structures. In these embodiments, the inputs to the treatmentplanning system 800 are integrated with Monte Carlo simulation of theplanned treatment plan and the effects of the plan, both therapeutic andpotentially toxic, can be simulated in real time. In some embodiments,geometric ray tracing models are used with estimates based on priorMonte Carlo simulation. Ray tracing models with prior Monte Carlosupport rapid and real time simulation of dosimetry.

The method depicted in FIG. 2E is as follows. Biometry measurements 820and user controls 875 such as structure and dose are entered into thetreatment planning system 800. Other inputs include information from aneye registration and imaging system 810. The output from the treatmentplanning system 800 consists of commands sent to the x-ray source andelectromotive subsystem to move and position the source as well as todirect the on and off times (dose control) of the x-ray source 830. Insome embodiments, maximum beam energy is set by the treatment planningsystem in order to create doses and plans for specific diseases. After adose 840 is delivered, the treatment planning system 800 then signalsx-ray source movement to deliver an additional dose 840. This cycle caniterate several times until the treatment is completed.

FIG. 2F depicts embodiments of the use of biometric measurements 910 tocreate an eye model and subsequently align a radiotherapy apparatus tothe eye 900 within the coordinate reference frame 940. In someembodiments, an A-scan ultrasound 910 is used to obtain biometric datasuch as axial length, anterior chamber depth, and corneal thickness,which can then be combined with measured parameters such as white-whitedistance and/or corneal thickness, and then entered into a computerizedmodel 920 that parameterizes the data and places the parameterized datainto the coordinate reference frame 940. Subsequent to this step, therobot is placed within the same coordinate reference frame 930 as theeye.

FIG. 2G depicts an arrangement 2700 to align the radiosurgical device2745. The goal of alignment is to align the output of the radiosurgicaldevice 2745 and optionally the laser pointer 2765 with the treatmentaxis 2735 or any other defined axis of the eye. When the device 2745 isaligned with the treatment axis, the device 2745 is alignedapproximately with a posterior pole 2720 of the eye. The posterior poleof the eye is approximately the position of the macula. In someembodiments, the collimator assembly is created so that the focusedradiation is applied to the entire posterior pole 2720 including theextension of the treatment axis 2735 to the posterior pole 2720 as wellas the macula. A camera 2740 is used to verify and/or maintain positionof the combined radiosurgery and laser pointing device. The camera canbase its verification on the eye contacting device 2730 or purely basedon imaging of visible structures on the eye.

In some embodiments, the camera 2740 detects the laser pointer positionand based on the position of the pointer on the target, theradiosurgical device is moved into an alternate position with the newlaser pointer position used to verify the position.

In some embodiments, patient fixation (depicted in FIG. 2H) on a targetis utilized to align the radiosurgical device to a visual axis 2790. Theline of site between an object and the retina is directed to the fovea,located at the center of the macula, which is an area the radiotherapysystems described herein are configured to treat. In some embodiments,the patient is requested to fixate on an object so that the visual axiscan be identified and the device aligned with this axis 2790. Thepatient fixes their eye on a fixation point 2770, which in someembodiments is a circular target. A line can be drawn between the objectand the center of the pupil 2780 which, when projected toward theposterior pole of the eye, intersects the macula or fovea 2760. In oneembodiment, the fixation point 2770 is the center of a circle so that aline through the center of the circle to the retina via the pupil center2780 is the visual axis. A lens 2772 is used to collimate or align lightfrom the fixation point 2770 so that the rays from the fixation point2770 do not diverge and the central region of the fixation point 2770can be used as the starting point for the visual axis. The visual axis2790, then, by definition, becomes the treatment axis in this embodimentin place of the geometric axis in other embodiments. Once this line isdefined in space, then the radiotherapy device can rotate about thisimaginary line, delivering the radiation beam 2750 to the target tissue,which is depicted as the fovea. The beam 2750 from the radiotherapydevice can then be placed at the proper angle to reach the macula 2760yet avoid the cornea 2785, lens 2777, and optic nerve 2775.

For example, if a single beam can deliver the desired amount ofradiation, the treatment planning system determines the direction of thex-ray beam relative to the patient specific anatomy and then the x-raysource is turned on. If two beams are desired to create the doseaccumulation to the target, then the treatment planning systemdetermines the size of the beams, their angles relative to the targetand the specific patient anatomy, then applies the first beam to the eyein a first angle and a second beam at a second angle relative to thetarget. A similar method is used for three, four, five, or six beams.

Monte Carlo Simulation and Experimental Validation

Monte Carlo (MC) simulations are used to model x-ray absorption,scatter, and dosing to structures impinged on by x-rays. Monte Carlomethods are a widely used class of computational algorithms forsimulating the behavior of various physical and mathematical systems,and for other computations. They are distinguished from other simulationmethods (such as finite element modeling) by being stochastic, that is,non-deterministic in some manner. Monte Carlo simulation forms anintegral part of all treatment planning systems and is used to assist intreatment planning where radiation is involved. Monte Carlo simulationcan also be used to predict and dictate the feasibility and otherelements of the radiotherapy system 10 (e.g., optimization of thecollimator and treatment planning schemes); for example, the collimationdesigns, the energy levels, and the filtering regimes, can be predictedusing Monte Carlo simulation. The designs predicted by Monte Carlosimulation should be experimentally verified and fine-tuned, but MCsimulation can predict the initial specifications. In some embodimentsof radiotherapy where the anatomy, beam energies, and treatment volumeare similar, the Monte Carlo simulations can be run once and then thepath variables altered (e.g., through ray tracing or other geometricmethodology) without need to go back to Monte Carlo simulation.

In some embodiments, MC simulation is integrated into the treatmentplanning systems and in other embodiments, MC simulation dictates thealgorithms used by the treatment planning system 800. MC simulation isoften used in the back end of the treatment planning system to createboundaries of treatment. For example, MC simulation can predict thepenumbra of an x-ray beam. The penumbra of the x-ray beam is used in thevirtual world to direct the x-ray beam and set boundary limits for thex-ray beam with respect to the lens, optic nerve, etc.

In some embodiments, age-related macular degeneration (AMD) is thedisease treated with the x-ray generation system. In some embodiments,the x-ray system 10 is used to treat post-surgical scarring inprocedures such as laser photocoagulation and laser trabeculotomy orlaser trabeculectomy. In some embodiments, the x-ray system is used totreat pterygia, ocular tumors or premalignant lesions such ashemangiomas and nevi. Importantly, the x-ray treatment system allows forselective irradiation of some regions and not others. In someembodiments, radiation is fractionated over a period of days, months, orweeks to allow for repair of tissues other than those which arepathologic or to be otherwise treated.

In order to 1) prove that lower energy radiation can be delivered to theretina to treat AMD in a clinically relevant time period with a deviceon the size scale in FIG. 1; 2) from a clinically relevant distance; and3) optimize some of the parameters of the treatment system for initialdesign specifications for the x-ray tube, an MC simulation wasperformed.

Eye geometry was obtained and a two-dimensional, then three-dimensionalvirtual model created, as shown in FIG. 5. Soft tissue and hard tissue(e.g., bone 2065) was incorporated into the model in FIG. 5. Axis 2082is the geometric axis, also termed the optical axis, of the eye. FIG. 6depicts different beam angles (2100, 2110, 2120, 2130, 2140) withrespect to the optical axis of the virtual eye which were modeled inthis system to simulate therapy to the macular region to treat AMD inthis example. In this simulation, each beam enters the eye at adifferent angle from the geometric central axis 2082. In this example,the geometric axis is assumed to be the treatment axis of the eye. Eachbeam cuts a different path through the eye and affects differentstructures, such as, for example, the macula 2094, optic nerve 2085,lens 2075, sclera 2076, cornea 2080, and fovea 2092 differentlydepending on the path through the eye. This modeling is used todetermine the angle of radiation delivery of the radiotherapy device andis incorporated into the treatment planning algorithm. For example, inFIG. 6, beam 2120 enters the eye directly through the eye's geometricaxis and beam 2100 enters through the pars plana. A series of x-rayenergies were modeled using a range of energies from about 40 keV toabout 80 keV. A proposed collimation scheme was used to produce a nearparallel beam as was a series of different filters (about 1 mm to about3 mm thickness aluminum). The combination of angle of entry of the beam,photon energy of the beam, and filtration of the beam all factor intothe relative amounts of energy deposition to the various structures.

FIGS. 7A-7E depict some of the results from the MC simulation with the80 keV energies showing that the x-ray beams can indeed penetratethrough the sclera 2200 and to the retina 2250 with minimal scatter toother ocular structures such as the lens 2260 and the optic nerve 2085.The higher density of dots indicate actual x-ray photons in the MCsimulation so that the relative absence of photons on the lens forexample (FIG. 7A) in certain beam angles is indicative of lack of photonabsorption at the level of the lens. These simulations reveal that lowenergy x-ray beams with widths up to 8.0 mm will substantially avoidcritical structures of the anterior portion of the eye at certain anglesoff of the central axis. This modeling is incorporated into treatmentplanning for each patient and for each disease being treated.

FIG. 7F (top picture) depicts the results of a simulation of a series ofbeams which enter the eye through the pars plana region. These anglesare the clock angles (a-h; counterclockwise looking at the eye and theirpenetration through the eye affects the structures of the front part ofthe eye similarly but affect the structures which are asymmetric behindthe eye (e.g., the optic nerve) differently. This simulation was done toplan how to minimize dose to the optic nerve while maximizing dose tothe target regions and can be performed for each patient with varyinggeometries. In some embodiments, simulations are performed by directingthe beam toward the eye through the pars plana direction and fromvarious clockface incident angles (a-h in FIG. 7F) which each correspondto varying nasal-temporal and caudal-cranial positions. In someembodiments, these beams are between about 2 mm and about 5 mm incross-section, such as diameter, and have an energy of between about 60keV and about 150 keV (also see FIG. 11H). Beams e, f, g, h, a which aregenerally directed from the inferior to superior direction and/or fromthe nasal to temporal direction, shown in FIG. 7F, have the most optimumprofile with respect to the optic nerve 2085 and lens 2260.

In some embodiments, certain angles or directions are identified ascorresponding to certain structures that are desirable to avoid duringtreatment. Consequently, the angles that correspond to these structuresare not used for the trajectory of the x-ray during treatment, thusavoiding the optic nerve. For example, in some embodiments, the angle b(FIG. 7F) may correspond with an x-ray trajectory that would passthrough the optic nerve 2085. In these embodiments, the angle b may notbe used to reduce the likelihood of exposing the optic nerve to thex-ray. Accordingly, the angles can be used to optimize the treatmentplan and present as little risk as possible to existing structures thatare sensitive to radiation. FIG. 7F depicts eight trajectory angles. Insome embodiments, the x-ray trajectory can include less than eight ormore than eight trajectory angles. For example, in some embodiments,four, six, ten, or twelve trajectory angles are presented. In theseembodiments, optimal beam directions are provided by those beams (e.g.,b, a, g, h, f) which are considered to come from the nasal direction.Beam entry angle on the sclera and its transmission to the retina arechosen by the treatment plan and are used to optimize radiotherapy totarget structures by the treatment planning system.

The lower picture in FIG. 7F shows the dose on the retina of one of theangled beams in the picture above. The predicted isodose fall-off forthese beams is greater than about 90% within about 0.05 mm to about 0.1mm of about a 1 mm to about a 2 mm beam which is less than ten percentgreater than the 100% isodose region. Region 2290 depicts a region ofhigher dose within the iso-dose profile. This higher dose region 2290results from the fact that the beam enters the eye at an angle. Theincrease in the dose is moderate at approximately ten to twenty percenthigher than the average for the entire region. Furthermore, becausethere are multiple beams entering the eye, the areas of increased dose2290 average out over the region of the retina. Therefore the higherdose region is incorporated into the treatment plan to account for theuneven distribution.

FIG. 8 is a quantitative, graphical representation of the data in FIGS.7A-7E. What is shown is the surface to retina dose for different x-raytube potentials and for different aluminum filter thicknesses 2385. Thisgraph is the data for beams 2100 and 2140 in FIG. 6. The ratio ofsurface to retina dose is shown in FIG. 8 (i.e., the dose of entry atthe sclera to the dose at the retina); what can be seen is that the doseto the sclera is not more than 3 times the dose to the retina for mostbeam energies (tube potentials). For energies greater than about 40 kVp,the ratio of surface dose to retina dose 2375 is less than about 3:1.What this says is that if the spot were maintained in the same positionas about 25 Gy was delivered to the retina, the maximum dose to thesclera would be about 75 Gy. Of course, as the beam is moved around theeye, the about 75 Gy is averaged over an area and becomes much less thanthe dose of about 25 Gy to the macula. This is depicted in FIG. 6 whichshows the results of the movement to different points along the sclerawith the x-ray beam. At 80 keV 2380, the ratio of surface to depth doseis closer to about 2.2 with about 1 mm of filtering. These data areintegrated into the treatment plan and the design of system 10 and, inpart, determine the time and potential of the x-ray tube. Thesurface-depth dose of the beam is also integral in determining thetreatment energy levels and corresponding tube potentials for variousdisease treatment and is therefore incorporated into the treatmentplanning system.

Therefore, in some embodiments, tightly collimated x-ray radiation atenergy levels greater than about 40 keV with greater than about 1 mm offiltration delivered through the pars plana region of the eye can beused to deliver a therapeutic dose of radiation to the retina with arelatively lower dose buildup on the sclera, the lens, or the opticnerve than the therapeutic dose delivered to the retina. For example, ifa therapeutic dose to the retina is about 25 Gy or less, the dose to anyregion of the sclera penetrated by the beam will be less than about 25Gy.

FIG. 9 is a bar graph representation showing scatter doses to ophthalmicregions other than the retina and comparing them to the retina. As canbe seen in the logarithmic figure, the dose to the lens 2400 (beams 2100and 2140) and optic nerve 2410 (beam 2140 alone), the two most sensitivestructures in the eye, are at least an order of magnitude lower than thedose delivered to the macular region 2450 of the retina. Other beamangles result in distinctly higher doses to these structures. Therefore,a 25 Gy dose of radiation can be delivered to a region of the retinathrough the pars plana region of the eye with at least an order ofmagnitude less radiation reaching other structures of the eye such asthe lens, the sclera, the choroids, and so forth. These simulationsdictate the design specifications for the x-ray generation systems andsubsystems. These simulations can also be integrated into the treatmentplanning system 800 as a component of the plan so that doses totherapeutic targets are higher than doses to critical structures. Forexample, the planning system, which incorporates the unique anatomy ofeach patient, can simulate the amount of radiation delivered to eachstructure dependent on the angle and position of delivery through thesclera. Depending on the angle, beam size, and beam energy, theradiation delivered to the ocular structures will vary and alternativedirection can be chosen if the x-ray dose is too high to the structuressuch as the lens and the optic nerve.

With reference to FIG. 10, to verify the validity of the MC simulationsand verify that the eye can be assumed to be a sphere of water, a humancadaver eye 2500 was obtained and the ratio of surface to depth dose ofan x-ray source was experimentally determined. Among other things,parameters of an emitted x-ray beam 2510 were compared with parametersof the beam 2520 emerging from the eye 2500. The ratio from theexperimental set-up in FIG. 10 proved to be identical to that when theeye is assumed to be water in the MC simulations. For example, the ratioof surface to 2 cm depth for 80 keV with 2 mm filtration was indeed 3:1as predicted by the MC model. Additional work verified that the dosefall off at each depth was likewise identical. This experimental workconfirms that the modeling predictions using MC are accurate for ocularstructures and that secondary interactions typically required of MCsimulations with high energy x-rays are not necessary for lower energyx-rays. These observations significantly simplify the MC simulations andallow for quick real time simulations at the time of treatment planningusing geometric relationships and predicted beam divergence.Furthermore, the design criteria which are used in the system 10 designcan be accurately modeled using water for their prediction rather thanthe time and expense involved in obtaining human tissue.

Further analysis and experimentation reveals that to deliver 25 Gy tothe macula in a clinically relevant time period (e.g., not longer than30 minutes), the system in FIG. 1 will draw about 1 mA to about 40 mA ofcurrent through the x-ray source. The exact number of mA depends on howclose the x-ray tube is to the eye and the maximum spectral energy(e.g., about 50 keV) delivered which is also dependent on the maximumpenetration depth desired. These parameters are integrated into atreatment plan which is used by the operator of the system to set thesystem parameters. If the tube is very close to the eye a low degree ofpenetration is desired, then the system will draw less current than ifthe system is further away from the eye. In some embodiments, it may bethat the about 15 Gy to about 25 Gy needs to be delivered to the retinain a period shorter than 10 minutes. In such embodiments, the tubecurrent may need to be upwards of 25 mA and the x-ray tube closer than25 cm from the retina. These parameters are for energies of about 60 toabout 100 keV and from about 1 mm to about 3 mm filtration withaluminum, lead, tungsten, or another x-ray absorbing metal. In certainembodiments, the collimator is less than about 5 cm from the anteriorsurface of the eye and the photon energy is about 100 keV with 1, 2, 3,4, or 5 beams with diameters of between about 1 mm and about 6 mmentering the eye through the infero-nasal region. The nasal regionaffords the greatest distance from the optic nerve and the inferiorregion is preferred so as to avoid the bones of the nose and theanterior skull. These assumptions are for an eye which is positioned tolook straight outward from the skull. In this embodiment, the treatmenttime may be less than about 5 minutes within a range of currents betweenabout 15 mA and about 40 mA. Each beam of the 1-4 beams can be turned onfor between about 3 seconds and about 5 minutes. In some embodiments, 3beams are used for the treatment. In some embodiments, the collimator isplaced within about 3 cm from the surface of the eye, and in someembodiments, the collimator is placed within about 10 cm of the surfaceof the eye.

FIG. 11A ¹ depicts the results of a single collimated x-ray beam 2600and FIG. 11A ² depicts the beam 2620 after it has penetrated throughapproximately 2 cm of water (an eye); the shaping collimator isapproximately 5.0 cm from the surface of the water. As can be seen inFIG. 11A ², there is a small penumbra width 2610 about an original beamwidth 2620 after penetration through the eye which is less than 10% ofthe shaping beam shown in FIG. 11A ¹. These data incorporate bothdivergence as well as isodose drop off from scatter and reveal that fora collimator within about 10 cm of the target, the penumbra can be verysmall. The beam energy in this example is approximately 80 keV. FIG. 11Bdepicts a graphical representation of the penumbra from measurementswithin an x-ray detection film. Delta 2650 represents the absorption inthe energy between the surface and the depth as recorded by x-raysensitive film. The tails seen in 2640 versus 2630 indicate a smalldegree of penumbra effect as the beam loses energy through the eye.Indeed, the penumbra for a 0.5 mm to 6 mm spot size can be as low asabout 0.01% and as high as about ten percent depending on the placementof the collimators with respect to the target.

FIGS. 11C-11G depict simulations of the summation of the beams asdescribed above. The simulation was accomplished using Monte Carlosimulation based on the device parameters discussed above, which createdthe experimentally verified single beam profiles shown in FIGS. 11A ¹and 11A². Alternatively, the beams can be created using ray tracinggeometries or geometric models of beams which are verified by the MonteCarlo simulation such that the error between the ray tracing and theMonte Carlo simulation is relatively constant given that beams travelthrough a similar amount of tissue with minor changes to beam width,beam energy, and amount of tissue through which the beam travels. InFIGS. 11C-11D, radiosurgical beams are depicted on an anterior portionof the eye in some embodiments of a method of delivery of radiosurgicalbeams. In FIG. 11C, traversal zones 3000 on the sclera 3010 of an eyeare depicted where radiosurgical beams are depicted traversing, orintersecting, the sclera 3010. Because the scatter and isodose fall ofthese beams are known to be low (e.g., within 10%), these beams can beplaced within one beam diameter of one another without substantialoverlap.

The angles of the beams with respect to the center of the posterior poleand the macular regions are determined by the eye model and treatmentplan. FIG. 11D depicts a saggital view of the beams depicted in FIG. 11Cwith the radiosurgical beams 3020 extending through the sclera andconverging at the macula region 3025. Radiosurgical beams 3020 can beplaced as little as about 100 microns apart and as far apart as about 2mm or about 3 mm depending on the target region to be treated. Beams3000 enter the sclera from the inferior or nasal region of the eye

Furthermore, it is now known based on modeling data, that the beams 3020can be placed about 50 microns to about 500 microns apart from oneanother at the target region without appreciable build up of dose onstructures such as the lens, the sclera, and the optic nerve. It is alsoknown from the modeling and experimentation that to deliver a dose ofgreater than about, for example, 20 Gy to a target region of the retina,greater than 1 beam can be advantageous, with treatment plans includingup to and beyond about 5 beams for delivering the desired radiationdose.

As described above, the surface to depth ratio of the beam to target isa factor in planning delivery of the dose. In the case of radiosurgicalbeams with energies in the 100 keV range, the surface to target dose canbe as low as about 2:1 or up to about 5:1. Within these ranges ofenergies and surface-to-target ratios, any particular region of thesclera will not receive an unacceptable dose of radiation. For example,with 4 beams and 24 Gy to the retina (6 Gy per beam) the dose to eachindividual region on the sclera is approximately 15 Gy, a dose that hasbeen determined to be well tolerated by the sclera. Indeed doses of upto 40 Gy can be tolerated well by the sclera. As shown by Pajic andGrener (Long-term results of non-surgical, exclusivestrontium-/yttrium-90 beta-irradiation of pterygia; Radiation andOncology 74 (2005) 25-29), doses up to even 50 Gy on the sclera is notharmful even up to 10 years later in young patients. In this case, 50 Gycould be delivered to a single point on the sclera and 18-24 Gydelivered to the macular region. Such a therapeutic regimen might thenrequire only beam.

FIG. 11E depicts a summation of the beams 3040 on the retina, andspecifically the macula in this example. Notably, the fall-off inpenumbra 3050 is very rapid at about 98% by a few millimeters from theedge 3060 of the beam.

FIG. 11F depicts embodiments of a summated beam in which an oblong shapeis created by collimators custom shaped to create a flared type ofradiosurgical spot 3070 on the region between the vascular arcades 3080which covers the macula.

FIG. 11G depicts embodiments of a target region in which there is acheckered appearance 3090 of the dose (microfractionation) caused bypassage through a collimator with multiple separate holes or collimatedregions. Such “microfractionation” can allow for improved therapy to thetarget region with reduced side effects. To the extent that side effectsare mediated by effects on the vasculature underlying the retina, bylimiting the amount of radiation to these blood vessels and allowing forlocal collateralization around each microfraction, the retinalvasculature can be spared without sacrificing therapeutic effect. Insome embodiments, origination of the neovascularization of the region isidentified and incorporated into the treatment plan. In suchembodiments, the radiation dose can be focused at this region to stopvascularization of the region. In some embodiments, a halo or annulartreatment region is identified and treated to stop or reducevascularization into a center portion of the halo or annular region.

FIG. 11H depicts a comparison on a brain CT 3170 between a finelycollimated orthovoltage radiosurgery beam 3100 and a prior art treatmentbeam 3105 in what has been attempted in the past (Marcus, et. al.,Radiotherapy for recurrent choroidal neovascularization complicatingage-related macular degeneration; Br. J. Ophthalmology, 2004; 88 pps.,114-119). In the prior art treatment beam 3105, large linearaccelerators were used without localization or customizationspecifically for the eye. The prior treatment beam path 3105 depicts theisodose calculations on the CT scan 3170. The figure depicts that the90-100% isodose volumes emcompass the ipsiliateral entire optic nerveand retina. Even the contralateral optic nerve 3106 received 63% 3107 ofthe dose. As a result, the treatments performed in Marcus et. al.required fractionation of the dose over many days and with smallfractions in order to prevent damage to normal tissues. Suchfractionation and minimalist dosing and planning schemes likely lead tothe lack of efficacy in those studies. In addition, these prior artattempt at applying radiation to the macula did not consider eyemovements or eye position.

In contrast, the beam path 3100 of a finely collimated orthovoltage beamis also depicted. This experimentally and theoretically verifiedmicrocollimated 100 keV beam enters the sclera in the pars plana region3110 delivering 18 Gy to the sclera and completely misses the opticnerve 3106, the lens 3115, and the cornea 3120, and delivering atherapeutic dose of 8 Gy to the macular region 3125. Thereafter, in thebrain, the radiation is scattered by the bone behind the eye to 1-2 Gy3135 and quickly attenuates to 0.5 Gy 3130 in the brain tissue and thebone of the skull 3180. With three of these beams at different clockangles on the eye, the summation on the macula will be 24 Gy, with only18 Gy to the sclera at three different entry points on the sclera.

FIG. 11I similarly depicts prior art treatment beams (Adams, J. et. al;Medical Dosimetry 24(4) 233-238). In this study, a proton beam study,the 90% isodose line 3230 encompasses the optic nerve 3210 and themacula 3200. In addition, eye location and movement were not controlledin this study. The authors of this study reported significantcomplications, likely due to the very broad coverage of the retina with20-24 Gy of proton beam radiation in 12 Gy fractions. Such complicationslikely negated any benefit of the therapy. The x-ray delivery describedherein allows for delivery only to the macula where the disease existswhile limiting or avoiding delivery of x-rays to other regions that arenot diseased,

FIG. 11J depicts a schematic of radiochromic film after benchtopdelivery of 100 keV overlapping x-rays at a target site 3250. The regionof overlapping x-ray beams 3275 are shown at their overlap region wherethe dose is 24 Gy. The optic nerve 3260 is depicted lateral to theoverlapping set of beams at a scaled distance from the center of theoverlap. A rapid isodose fall off 3273, 3277 occurs lateral to theoverlapping region 3275 and well away from the optic nerve 3260.Notably, the isodose depicted at region 3265 is indeed between about 1%and about 10% of the dose (0.24 Gy-2.4 Gy) at the treatment spot 3275.These data are a consequence of the overlapping beam geometry as well asthe fine beam collimation; they are physical proof of the ability offinely collimated overlapping orthovoltage x-ray beams to createwell-defined treatment regions. Due to the 10-100 fold difference intreatment dose to optic nerve dose, fractionation is not required, andthe entire dose can be given to the treatment region in one session withminimal concern for injury to important structures, such as the opticnerve. These overlap regions can be optimized and/or placed anywherewithin the eye which is determined by the treatment planning system anddepends on the beam energies, collimation, and filtering. The degree ofoverlap is also to an extent determined by system parameters. Forexample, treatment of the entire region of the retina for maculardegeneration may be different than that for tumors or for hemangioma.

These modeling techniques, parameters, and imaging system describedabove allow for an integrated system to be devised and developed. Someembodiments are depicted in FIG. 12A in which a five degree of freedompositioning stage is used so as to produce the desired beam angles todeliver radiosurgery to the retina. The collimator 3315 is positionedclose to the eye of the patient 3330, so as to allow for an acceptablepenumbra as well as a tightly collimated radiation beam as describedabove. The collimator is typically between about 1 mm and about 4 mm sothat the spot size on the back of the retina is approximately about 4min to about 7 mm. Laser pointer 3225 travels through a beam splitterand exits the collimator with its center aligned with the radiationbeam. Region 3335 is the space through which the device can move. Thespace can be planned based on imaging performed on the patient. Thespace is a small region which allows for simplification of the motionsystem moving the x-ray source 3325. The system 3300 also contains ahose system 3310, 3345 to deliver cooling fluid into and from the x-raytube 3325.

FIG. 12B depicts a cross-section schematic view of the system 3300treating a patient's eye 3460. Laser pointer 3225 directs beam 3415 to abeamsplitter 3420 and out the collimator centered within the x-ray beam.The x-ray anode 3400 has a greatest dimension between about 50 micronsand about 5 mm and can be placed from about 50 mm to about 200 mm fromthe retina. Maintaining the anode 3400 at this distance from the retinain one embodiment allows maintaining a low penumbra. The radiation beam3410 is delivered through the collimator 3315, and its diverging pathenters the eye approximately in the pars plana region 3470, missing theimportant structures of the anterior chamber such as the lens and thecornea. In some embodiments, a lens 3450 contacts the sclera or thecornea of the eye 3460 and can be used as a fiducial to direct theradiotherapy system. The collimator is typically within about 1 cm toabout 12 cm from the beam entry point on the sclera.

FIG. 12C depicts the clinical flow involving the radiotherapy device. Animaging modality and physical exam 3500 are used to create an eye model3510, through which a 3D coordinate map is generated. The dose for aspecific disease is chosen as is the maximum beam energy based on theregion to be treated as well as the region to be avoided. Thesevariables can be determined by treatment software as well as physicianinput related to the disease as well the depth of the diseased tissue.The patient is then positioned, and the optional contacting device isplaced against or close to the eye of the patient 3520. The patient andguide are aligned with the guide 3530, and the treatment of a dose ofradiation is applied 3540.

FIG. 12D depicts a therapeutic set-up in which the radiotherapy deviceis aligned to a needle 3600 placed at least partially through the sclera3620 and even into the vitreous 3630 of the eye. A light guide 3700, orpointer, can be placed into or coupled with the needle to illuminate theretina with a collimated light source. The needle 3600 and light guide3700 can be stabilized within the sclera 3620 so that the collimatedlight source is stable on the point on the retina. The radiotherapydevice can then be aligned with the needle 3600 and as such will deliverradiation in a straight line along the needle and along the light guidepath and to the desired region of the retina. With this set-up, smallregions of the retina can be precisely targeted.

Combination Therapy

Radiotherapy device 10 can be used in combination with othertherapeutics for the eye. Radiotherapy can be used to limit the sideeffects of other treatments or can work synergistically with othertherapies. For example, radiotherapy can be applied to laser burns onthe retina or to implants or surgery on the anterior region of the eye.Radiotherapy can be combined with one or more pharmaceutical, medicaltreatments, and/or photodynamic treatments or agents. As used herein,“photodynamic agents” are intended to have their plain and ordinarymeaning, which includes, without limitation, agents that react to lightand agents that sensitize a tissue to the effects of light. For example,radiotherapy can be used in conjunction with anti-VEGF treatment, VEGFreceptors, steroids, anti-inflammatory compounds, DNA binding molecules,oxygen radical forming therapies, oxygen carrying molecules, porphyrynmolecules/therapies, gadolinium, particulate based formulations,oncologic chemotherapies, heat therapies, ultrasound therapies, andlaser therapies.

In some embodiments, radiosensitizers and/or radioprotectors can becombined with treatment to decrease or increase the effects ofradiotherapy, as discussed in Thomas, et al., Radiation Modifiers:Treatment Overview and Future Investigations, Hematol. Oncol. Clin. N.Am. 20 (2006) 119-139; Senan, et al., Design of Clinical Trials ofRadiation Combined with Antiangiogenic Therapy, Oncologist 12 (2007)465-477; the entirety of both these articles are hereby incorporatedherein by reference. Some embodiments include radiotherapy with thefollowing radiosensitizers and/or treatments: 5-fluorouracil,fluorinated pyrimidine antimetabolite, anti-S phase cytotoxin,5-fluorouridine triphosphate, 2-deoxyfluorouridine monophosphate(Fd-UMP), and 2-deoxyfluorouridine triphosphate capecitabine, platinumanalogues such as cisplatin and carboplatin, fluoropyrimidine,gemcitabine, antimetabolites, taxanes, docetaxel, topoisomerase Iinhibitors, Irinotecan, cyclo-oxygenase-2 inhibitors, hypoxic cellradiosensitizers, antiangiogenic therapy, bevacizumab, recombinantmonoclonal antibody, ras mediation and epidermal growth factor receptor,tumor necrosis factor vector, adenoviral vector Egr-TNF (Ad5.Egr-TNF),and hyperthermia. In some embodiments, embodiments include radiotherapywith the following radioprotectors and/or treatments: amifostine,sucralfate, cytoprotective thiol, vitamins and antioxidants, vitamin C,tocopherol-monoglucoside, pentoxifylline, alpha-tocopherol,beta-carotene, and pilocarpine.

Other agents include complementary DNAs, RNA, micro-RNA inhibitors(e.g., U.S. Pat. No. 7,176,304, incorporated herein by reference), andSiRNAs (e.g., see U.S. Pat. No. 7,148,342, incorporated herein byreference), all of which can be combined with radiation treatment. Insome embodiments, these agents are provided with radiation treatment toimprove tumor control; treat inflammatory conditions; and prevent,reduce, limit, or stabilize angiogenesis.

Antiangiogenic Agents (AAs) aim to inhibit growth of new blood vessels.Bevacizumab is a humanized monoclonal antibody that acts by binding andneutralizing VEGF, which is a ligand with a central role in signalingpathways controlling blood vessel development. Findings suggest thatanti-VEGF therapy has a direct antivascular effect in human tissues. Incontrast, small molecule tyrosine kinase inhibitors (TKIs) preventactivation of VEGFRs, thus inhibiting downstream signaling pathwaysrather than binding to VEGF directly. Vascular damaging agents (VDAs)cause a rapid shutdown of established vasculature, leading to secondarytissue death. The microtubule-destabilizing agents, includingcombretastatins and ZD6126, and drugs related to5,6-dimethylxanthenone-4-acetic acid (DMXAA) are two main groups ofVDAs. Mixed inhibitors, including agents such as EGFR inhibitors orneutralizing agents and cytotoxic anticancer agents can also be used.

Radiodynamic Therapy

Radiodynamic therapy refers to the combination of collimated x-rays witha concomitantly administered systemic therapy. As used herein, the term“radio dynamic agents” is intended to have its ordinary and plainmeaning, which includes, without limitation, agents that respond toradiation, such as x-rays, and agents that sensitize a tissue to theeffects of radiation. Similar to photodynamic therapy, a compound isadministered either systemically or into the vitreous; the region in theeye to be treated is then directly targeted with radiotherapy using theeye model described above. The targeted region can be preciselylocalized using the eye model and then radiation can be preciselyapplied to that region using the PORT system and virtual imaging systembased on ocular data. Beam sizes of about 1 mm or less can be used inradiodynamic therapy to treat ocular disorders if the target is drusenfor example. In other examples, the beam size is less than about 6 mm.

Other compounds that can increase the local efficacy of radiationtherapy are metallic nanoparticles, such as gold, silver, copper, orcombinations thereof. These particles can further be tagged withtargeting binding agents so that the nanoparticles can bind to targetson blood vessels or macrophages to target higher doses of radiation tospecific areas of the patient. For example, Carter et. al. (JournalPhysical Chemistry Letters, 111, 11622-11625) report improved andenhanced targeting using nanoparticles of gold. They further report evenfurther targeting with targeting agents cross-linked to the goldparticles. These nanoparticles can be combined with highly localizedradiotherapy during treatment

Other Applications for Portable Orthovoltage Radiotherapy

The devices and methods described in this application can broadly beapplied to body structures outside the eye. For example, there are manydiseases which can be treated with portable orthovoltage stereotacticradiosurgery and the convenience of the therapy radio surgical devices.The finely collimated beams and laser targeting are elements of thedisclosure that can be utilized in a myriad of other treatmentparadigms. For example, almost any pathology physically exposed during asurgical procedure can be treated with orthovoltage radiotherapy,including surgery of the skin and soft tissue, brain (FIG. 15), neck(FIG. 17), Breast (FIG. 14), Musculoskeletal System (FIG. 16),Peripheral Vascular System (FIGS. 17 and 20), uterus (e.g., endometrialor stromal pathology), and bioartificial materials (e.g., hernia meshes,vascular grafts, vascular patches, prosthetics, etc.) The primarydisease can be treated or a condition considered secondary to theprimary disease or surgery can be treated. Automated positioning systemscan be utilized or manual positioning systems can be utilized to applythe therapy. The energy level (e.g., from about 40 KeV to about 500 KeV)can be chosen depending on the depth of the pathology and the type ofcondition being treated. The fine dose control described above whichutilize small collimators with tight penumbras enable treatment of otherbody regions safely and in a controlled manner.

In some embodiments, a system, for treating a target tissue with x-rayradiation, can include a radiation source that emits x-rays, the x-rayshaving an energy between about 1 KeV and about 300 KeV. The x-rayenergies and ranges can also be similar to those discussed elsewhere inthis disclosure. The system can also include a collimator thatcollimates the emitted x-rays into an x-ray beam, the collimator havingan inner cross-sectional dimension. The x-ray beam can have a dosedistribution at a beam spot in a plane at the target tissue as discussedelsewhere in this disclosure. For example, a dose of the x-ray beam at aregion within the plane can be less than about 20%, 10%, 5%, or 1% ofthe dose at a centroid, or center, of the beam spot; wherein the regionis located at a distance, away from the centroid of the beam spot, equalto about 70% of the inner cross-sectional dimension. In someembodiments, the distance can be about 80%, 60%, 50%, 40%, 30%, or 20%of the inner cross-sectional dimension. The system can also include analignment system that aligns the x-ray beam with an axis traversing thetarget tissue and that positions the radiation source within about 50 cmfrom the target tissue. In some embodiments, the radiation sourceincludes a collimator and can be positioned within about 40 cm, 30 cm,20 cm, 10 cm, and 5 cm. The system can also include a processing modulethat receives an input comprising a parameter of the target tissue andthat, based on the parameter, outputs to the alignment system adirection for the x-ray beam to be emitted toward the target tissue.

Some embodiments described herein provide a system, for treating atarget tissue with radiation, including a radiation source that emitsx-ray radiation during a treatment session and that collimates theemitted x-ray radiation into a x-ray beam having a cross-sectionaldimension of less than about 6 mm as the beam exits the collimator. Insome embodiments, the cross-sectional dimension of the x-ray beam isless than about 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. The system can alsoinclude a mapping module that repeatedly maps a location of the targettissue to a coordinate system during the treatment session; a movementmodule that directs the emitted x-ray radiation along a trajectory thatis based, at least in part, on at least one mapped location of thecoordinate system; and a targeting module that emits a target light thatindicates an approximate center of a beam spot of the x-ray beam.

In some embodiments, a method, of applying x-ray radiation to targettissue, is described. The method can include obtaining imaging dataindicative of a target tissue; identifying, based on the imaging data, alocation of the target tissue; repeatedly mapping the location of thetarget tissue in the coordinate system, thereby producing mappedlocations of the target tissue in the coordinate system; positioning,based on the mapped locations of the target tissue in the coordinatesystem, an x-ray collimator that directs an x-ray beam to the targettissue; and emitting the x-ray beam from the collimator to the targettissue, the x-ray beam having an energy of from about 1 KeV to about 500KeV. In some embodiments, the x-ray beam has a dose distribution at abeam spot in a plane at the target tissue, such that a dose of the x-raybeam at a region within the plane and outside the beam spot is less thanabout 20% of a dose at a centroid, or center, of the beam spot. In someembodiments, the dose of the x-ray beam at the region within the planeand outside the beam spot is less than about 15%, 10%, 5%, or 1% of thedose at the centroid, or center, of the beam spot

For example, collimated x-ray beams can be used in the surgical theater,as illustrated in FIG. 13, with a patient 4000 in a supine position. Thesmall, lightweight size of the radiotherapy device 4120 allows it to beattached to the operating table or stored in a convenient spot until itis used, at which point it can be brought out or wheeled into theoperating room and attached to the table. An operator interface 4160 canbe used to plan or monitor the treatment with the portable orthovoltagedevice. The operator interface 4160 can allow the operator of the deviceto direct and plan a radiotherapy to the patient 4000, similar to whatis described above for treatment of ocular pathology. One or morerobotic arms 4100 can direct the radiotherapy device 4120 to deliverx-rays to a region 4150 of pathology accessible to orthovoltage x-rays(e.g., less than about 5 cm deep within the tissue). The region 4150 canbe registered using the x-ray tube 4120 with imaging or with a needle orother fiducial marker which is inserted into the region 4150, and afterwhich, the device is targeted to the region 4150. In some embodiments,the tumor or pathology is exposed during a surgical procedure, in whichtissue overlying the region 4150 is moved or separated. The beam energylevels (e.g., 30 KeV, 60 KeV, 100 KeV, or 200 KeV) are chosen by thedevice operator depending on the disease which is being treated. In somediseases that are superficial, such as skin cancer, a lower energy beammay be desired, so as not to have too much penetration into the skin.When a deeper disease is being treated such as a blood vessel or tumor,a higher beam energy may be desired. The treatment planning softwareallows for the chosen energy to be applied to the therapy.

In some embodiments, as illustrated in FIG. 14A, treatment of a breasttumor using orthovoltage radiotherapy is provided. Orthovoltage x-raydevices 4520 are depicted delivering highly collimated beams 4530 ofx-rays to a region 4550 of breast pathology. Depending on the depth ofthe pathology, a beam energy in the range of from about 40 KeV to about200 KeV may be chosen. In FIG. 14A, the treatment is delivered throughthe skin to the tumor or other breast lesion. In this case, a CT scan,ultrasound, or other imaging unit 4560 (illustrated in FIG. 14B) can beused to image the region 4550 and assist to develop the treatment planfor the device. During treatment, the x-ray devices 4520 are positionedclose to the tumor and breast (e.g., from about 5 cm to about 14 cm), asdepicted in FIG. 14A and described above in connection with thetreatment of the eye. The collimator attached to the x-ray device 4520and positioned in proximity to the skin above the lesion provides atightly collimated beam spot size. The collimator for the x-ray device4520 is positioned close to the pathology of interest in order toprovide and maintain a small penumbra.

FIG. 14B depicts some embodiments of x-ray delivery with a percutaneousneedle 4600 inserted into the region of pathology. The orthovoltageradiotherapy can be applied during a procedure to remove the tumor orindependently, prior to, after, or in place of surgery. The percutaneousneedle 4600 can provide a treatment axis or serve a similar function asthe treatment axis described above. In this respect, the percutaneousneedle 4600 can be used to align the radiotherapy device and delineate atreatment zone around the tip of the needle, where the angle to the tipof the needle can be defined by a relationship between the tip of theneedle and the edge of the radiotherapy collimator.

The orthovoltage therapy can also be applied in combination with othertherapies or in combination with chemotherapy which is applied eithersuperficially or systemically, or even injected directly into thepathologic bed. Notably, as described above, the orthovoltage system'sability to deliver highly collimated beams using the collimator andlaser targeting systems described above facilitate discreet delivery toregions of pathology. Such precise delivery enables precise and accuratetargeting with minimal scatter to normal tissues, as described inrelation to the ocular pathology above.

FIG. 15 depicts embodiments of a neurosurgical procedure 5000 in whichorthovoltage radiotherapy devices 5050 are brought into proximity of apathologic region 5300, and radiotherapy beams 5060 are directed towardthe region 5300. The pathology can be a tumor, arteriovenousmalformation, region of hyper-reactivity, inflammatory region, seizurefocus, etc. The radiotherapy can be introduced into the brain tissueusing burr holes 5100 or in some cases, a craniotomy. After exposure orremoval of the pathology 5300, the tumor bed can be exposed toorthovoltage radiotherapy delivered through the burr hole directly tothe tumor bed. The beams, collimated to diameters less than about 1.0 cmand even to diameters less than 6 mm, can be directed to the pathologicregion 5300 through a small burrhole 5100. The light pointer (laserpointer in some embodiments) emits a laser 5260 that is coupled to or iscollinear with the x-ray beam and enables direction of the x-ray source5050 to the correct position. In the case of an intra-operative therapy,the surgeon can direct the x-ray to the pathologic region 5300 becausehe/she can see the region directly. With highly collimated x-ray beamswith tight penumbras, x-ray therapy can be delivered to pathologicregions 5300 in high doses while avoiding critical structures asproposed above for ocular applications. Depending on the desired depthof treatment, the radiotherapy device can be run at beam energies fromabout 30 KeV to about 100 KeV. Similarly, needle 5200 can be used to aidin guiding the radiotherapy or can act as a therapy to work incombination with the radiotherapy such as for example, an additionaloxygenation stream.

FIGS. 16A and 16B depict the use of portable orthovoltage radiotherapyfor the treatment of musculoskeletal disease 5500, in this case carpaltunnel syndrome. The orthovoltage device 5550 can emit beams 5570 thatare used to treat inflammatory conditions of the musculoskeletal systemsuch as carpal tunnel syndrome where the nerves and/or tendons of thedistal forearm are trapped or inflamed. The use of the radiotherapy cancomplement surgery, be used in place of surgery, or can complementpharmaceutical therapy such as steroid therapy. In some embodiments, thetreatment can be applied through an opening 5560 created in tissueoverlying the disease 5500. Other musculoskeletal conditions includespinal stenosis, inflammatory arthidites, implants and associatedpost-surgical inflammation, hip, knee, and other replacements, etc.

FIGS. 17A and 17B depict delivery of orthovoltage x-ray beams 6060 fromradiotherapy devices 6050 to regions of peripheral vascular disease6000. FIG. 17A depicts x-ray delivery through skin overlying theperipheral vessels 6100. Radiotherapy may be applied to the disease ofvulnerable carotid lesions or may be applied to the carotid at or afterthe time of a stent or other material being placed. FIG. 17B depictsdelivery of x-ray beams 6060 through a surgically opened region 6200 toexpose vessels 6210. Radiotherapy beam energy, beam width, and directioncan be chosen in accordance with the tissue, disease, and time totreatment. For example, in some embodiments, during an open surgery asdepicted in FIG. 17B, the beam energy may be chosen so as to be about 40KeV or about 50 KeV depending on the tissue penetration required. Thedisease to be treated may be prevention of restenosis or treatment ofhyperplasia, treatment of vulnerable atherosclerotic plaques present inthe vessel. In some embodiments, the radiotherapy is delivered in onefraction of about 10 Gy to about 50 Gy and in some embodiments, theradiotherapy is delivered in doses of about 5 Gy to about 10 Gy inseveral fractions, which can be applied through different trajectories,as discussed in other embodiments. The radiotherapy can be combined withpharmaceutical therapy prior to or after the institution ofradiotherapy. The pharmaceutical therapy can consist of any of thecompounds listed above and can be delivered locally or systemically toreach the site.

FIG. 18 depicts the use of portable orthovoltage radiotherapy duringopen surgical procedures in the abdomen 7000 by directing x-ray beams7060 from radiotherapy devices 7050 toward a treatment site 7010. Insome embodiments, multiple beams 7060 may intersect at a point 7020 thatis at or near the treatment site 7010. For example, tightly collimatedbeams 7060 with small penumbras can be applied to surgical planes duringor after an operation to treat colon cancer. With the light/laserpointer, the surgeon can evaluate the exact position of the x-ray andapply x-ray in a controlled manner to the pathology of interest. Thebeam energy can be chosen for intra-operative treatment such as forexample, about 40 KeV, about 50 KeV, or 60 KeV. In some embodiments, thebeam energy can be less than about 40 KeV or greater than about 60 KeV.Moreover, in some embodiments, the beam energy can be between about 40KeV and about 60 KeV.

In FIG. 18, the portable radiosurgery device is used to treatgastrointestinal cancers (e.g., colorectal cancer, stomach cancers,hepatobiliary cancers, sarcomas, etc.) in which residual microscopictumor may be left behind within a patient. A portable orthovoltageradiosurgery device can brought into the operating room and anappropriate energy level chosen to treat the surgical area with thedevice. In some embodiments, an energy level of about 40 KeV is chosenas this energy level does not penetrate tissue very well and can be usedto treat the peritoneum or lymph nodes post-operatively.

During an open surgery when all the tissues are exposed, the lasertargeting portion of the radiotherapy device can be used by the surgeonto direct the therapy to the correct region enabling the physician toknow where the x-ray beam is pointed. For adjunctive treatment withsurgery and because the tissues are superficial, the energy level of thedevice can be chosen such that there is limited exposure to otherregions around the plane of dissection. Other than colon cancer, diseasesuch as inflammatory bowel disease, motility disorders, irritable bowel,and the like, can be treated with radiotherapy as well.

FIG. 19 depicts embodiments of a radiotherapy system 7500 that providestreatment of disease of the gastrointestinal tract where theradiotherapy is applied in the form of an x-ray beam 7560 from aradiotherapy device 7550 located outside the patient. Such therapy canbe combined with endoscopy so as to direct the radiotherapy to correctlocation. In FIG. 19, the radiotherapy devices 7550 are directed throughthe skin of the abdominal wall to treat a lesion 7510 of the largebowel. Radiotherapy devices 7550 can act simultaneously or independentlyto apply radiotherapy to the large bowel lesion 7510. Similarly, in someembodiments, a lesion on the liver 7520 can be treated withradiotherapy.

FIG. 20 depicts a dialysis shunt graft 8000 where a Goretex tube 8030carries blood between vessels 8040 (e.g., from the artery to the vein)and needles are placed inside the graft to remove blood from thepatient, filter it, then replace it into the patient. These grafts tendto become stenotic over time with scar tissue growing along anastamosisends 8020. Radiotherapy can be applied through x-ray beams 8010 emittedfrom radiotherapy devices 8050 to these grafts to limit, reduce, and/orprevent such growth (Kelly et. al. Int. J. Radiat. Oncol Biol Phys 200254(1) 263-9, incorporated herein by reference) over the region of theanastamosis. The x-ray beams 8010 can be applied such that they havelittle penetrating ability (e.g., with an energy of about 30 KeV in someembodiments), yet will treat the evolving stenosis at the anastomosis.The radiotherapy can be applied at the time of surgery or as anadjunctive to palliative treatments to maintain patency of the dialysisgrafts.

FIG. 21 depicts an additional use for radiotherapy devices 8550. In thisfigure, small animals are being treated with radiotherapy usingembodiments of radiotherapy devices described herein. The finelycollimated beams 8560 are used to treat and study the effects ofradiation and potentially pharmaceutical therapy in combination withradiation therapy on small animals. A stage can be established where theanesthetized animal is restrained under anesthesia, and the animal canbe held in a preferred orientation by restraints. The finely collimatedradiotherapy beams are directed to the animal region and the dosageapplied to the region of interest within the animal. The small, finelycollimated beams (e.g., as small as about 50 microns in diameter) areutilized to carefully study the dose effects of x-rays on small animals(e.g., rats, mice, rabbits, guinea pigs, etc.). The laser pointerco-aligned with the x-ray is helpful in marking direction and target ofthe x-rays on the small animal.

FIG. 22 depicts a drug evaluation system 9000 in which an orthovoltagex-ray tube 9010 is mounted on a robotic arm and is utilized forunderstanding the effect of orthovoltage x-rays on different cell types,tissue types, and systems. The table top carries a platform 9040 forcell and tissue culture 9030. The robotic arm can be positioned at anyposition along the table top. The computer and associated software canbe used to program and control the dose of radiation delivered to thetissue culture 9030. Evaluation systems such as this one are novelbecause of the finely collimated beams 9020 of radiation which can bedelivered. The dose of x-ray, its direction, its beam energy, and thebeam size can all be precisely controlled as described above. Suchprecision allows for careful study of x-ray effects on cell culture,tissue culture, and/or organ culture. A software program can adjust thebeam width, beam energy, the length of time the beam is emitted, whichultimately controls the total delivered energy, and other beamparameters. The robotic arm can be moved about the cell culture systemand deliver x-ray energy at different levels to the cell culturesystems. This system allows for the evaluation of the effects ofradiation on individual cells, radiation effects in combination withvarious pharmaceuticals, and radiation effects on cell and tissueculture systems.

While certain aspects and embodiments of the disclosure have beendescribed, these have been presented by way of example only, and are notintended to limit the scope of the disclosure. Indeed, the novel methodsand systems described herein may be embodied in a variety of other formswithout departing from the spirit thereof. The accompanying claims andtheir equivalents are intended to cover embodiments of such forms ormodifications as would fall within the scope and spirit of thedisclosure.

1. A system, for treating a target tissue of an eye with x-rayradiation, comprising: a radiation source that emits x-rays; acollimator that collimates the emitted x-rays into an x-ray beam, thex-ray beam having a dose distribution at a beam spot in a plane at thetarget tissue of the eye; an alignment system that aligns the x-ray beamwith an axis traversing the target tissue and based on an inputcomprising a parameter of the target tissue, directs the x-ray beam tobe emitted toward the target tissue; a fiducial marker; and a holderthat stabilizes the eye during emission of the x-ray beam; wherein theparameter comprises a location of the fiducial marker that providesindication of a location of the target tissue; and wherein the fiducialmarker comprises a component of the holder.
 2. The system of claim 1,wherein the alignment system is configured to align the x-ray beamrepeatedly during a treatment session.
 3. The system of claim 1, furthercomprising an imaging system that determines the axis traversing thetarget tissue.
 4. The system of claim 1, wherein said axis comprises ageometric axis of the eye.
 5. The system of claim 1, wherein said axiscomprises a visual axis of the eye.
 6. A system, for treating a targettissue with x-ray radiation, comprising: a radiation source that emitsx-rays; a collimator that collimates the x-rays into an x-ray beam, theradiation source comprising an imageable light source that indicates anapproximate center of a beam spot of the x-ray beam at the targettissue; an alignment system that aligns the x-ray beam with an axistraversing the target tissue and that positions the radiation sourcesuch that a trajectory of the x-ray beam traverses the target tissue;and a processing module that outputs to the alignment system a directionfor the x-ray beam to be emitted toward the target tissue based on aparameter of the target tissue, the parameter comprising a location of afiducial marker that provides indication of a location of the targettissue; an eye holder that engages the eye during emission of the x-raybeam, the eye holder comprising the fiducial marker.
 7. The system ofclaim 6, wherein the imageable light source comprises a laser.
 8. Thesystem of claim 6, wherein the alignment system further comprises aprogrammable electromotive system to move the x-ray source.
 9. Thesystem of claim 6, wherein the collimator is configured to collimate thex-ray beam such that the x-ray beam has a penumbra at the target tissueof less than about 20 percent.
 10. The system of claim 6, wherein thealignment system positions the radiation source within about 50 cm fromthe target tissue.
 11. A system, for treating a target tissue of an eyewith x-ray radiation, comprising: an x-ray radiation source; an eyeholder that engages an eye; an alignment system, coupled to theradiation source, the alignment system having a coordinate systemdefining an axis traversing the target tissue; and a processing modulethat outputs to the alignment system a direction for radiation emittedfrom the radiation source toward the target tissue; wherein said targettissue comprises the eye and said axis traversing the eye is determinedby a fiducial marker on the eye holder.
 12. The system of claim 11,further comprising an imaging system that determines the axis traversingthe target tissue.
 13. The system of claim 11, wherein said targettissue comprises an eye and said axis traversing the plane of the eye isdetermined by an anatomic feature of the eye.
 14. The system of claim11, wherein said processing module outputs a position for the radiationsource.
 15. The system of claim 11, wherein said axis comprises ageometric axis of the eye.
 16. The system of claim 11, wherein said axiscomprises a visual axis of the eye.
 17. The system of claim 11, furthercomprising a collimator that is configured to collimate the radiationsuch that the radiation has a penumbra at the target tissue of less thanabout 20 percent.
 18. The system of claim 11, wherein the alignmentsystem positions the radiation source within about 50 cm from the targettissue.